id sid tid token lemma pos admet-144 1 1 manuscript manuscript PROPN admet-144 1 2 doi doi PROPN admet-144 1 3 : : PUNCT admet-144 1 4 10.5599 10.5599 NUM admet-144 1 5 / / SYM admet-144 1 6 admet.3.1.144 admet.3.1.144 PROPN admet-144 1 7 1 1 NUM admet-144 1 8 admet admet X admet-144 1 9 & & CCONJ admet-144 1 10 dmpk dmpk PROPN admet-144 1 11 3(1 3(1 NUM admet-144 1 12 ) ) PUNCT admet-144 1 13 ( ( PUNCT admet-144 1 14 2015 2015 NUM admet-144 1 15 ) ) PUNCT admet-144 1 16 1 1 NUM admet-144 1 17 - - SYM admet-144 1 18 14 14 NUM admet-144 1 19 ; ; PUNCT admet-144 1 20 doi doi NOUN admet-144 1 21 : : PUNCT admet-144 1 22 10.5599 10.5599 NUM admet-144 1 23 / / SYM admet-144 1 24 admet.3.1.144 admet.3.1.144 ADV admet-144 1 25 open open ADJ admet-144 1 26 access access NOUN admet-144 1 27 : : PUNCT admet-144 1 28 issn issn PROPN admet-144 1 29 : : PUNCT admet-144 1 30 1848 1848 NUM admet-144 1 31 - - SYM admet-144 1 32 7718 7718 NUM admet-144 1 33 http://www.pub.iapchem.org/ojs/index.php/admet/index http://www.pub.iapchem.org/ojs/index.php/admet/index NOUN admet-144 1 34 review review VERB admet-144 1 35 the the DET admet-144 1 36 extended extended ADJ admet-144 1 37 clearance clearance NOUN admet-144 1 38 model model NOUN admet-144 1 39 and and CCONJ admet-144 1 40 its its PRON admet-144 1 41 use use NOUN admet-144 1 42 for for ADP admet-144 1 43 the the DET admet-144 1 44 interpretation interpretation NOUN admet-144 1 45 of of ADP admet-144 1 46 hepatobiliary hepatobiliary ADJ admet-144 1 47 elimination elimination NOUN admet-144 1 48 data datum NOUN admet-144 1 49 gian gian PROPN admet-144 1 50 camenisch*,1 camenisch*,1 PROPN admet-144 1 51 , , PUNCT admet-144 1 52 julia julia PROPN admet-144 1 53 riede1,2 riede1,2 PROPN admet-144 1 54 , , PUNCT admet-144 1 55 annett annett PROPN admet-144 1 56 kunze1 kunze1 PROPN admet-144 1 57 , , PUNCT admet-144 1 58 jΓΆrg jΓΆrg PROPN admet-144 1 59 huwyler2 huwyler2 PROPN admet-144 1 60 , , PUNCT admet-144 1 61 birk birk PROPN admet-144 1 62 poller1 poller1 NOUN admet-144 1 63 and and CCONJ admet-144 1 64 kenichi kenichi PROPN admet-144 1 65 umehara1 umehara1 PROPN admet-144 1 66 1 1 NUM admet-144 1 67 division division NOUN admet-144 1 68 of of ADP admet-144 1 69 drug drug NOUN admet-144 1 70 metabolism metabolism NOUN admet-144 1 71 and and CCONJ admet-144 1 72 pharmacokinetics pharmacokinetic NOUN admet-144 1 73 , , PUNCT admet-144 1 74 integrated integrate VERB admet-144 1 75 drug drug NOUN admet-144 1 76 disposition disposition NOUN admet-144 1 77 section section NOUN admet-144 1 78 , , PUNCT admet-144 1 79 novartis novartis NOUN admet-144 1 80 institutes institutes PROPN admet-144 1 81 for for ADP admet-144 1 82 biomedical biomedical ADJ admet-144 1 83 research research NOUN admet-144 1 84 , , PUNCT admet-144 1 85 ch-4056 ch-4056 PROPN admet-144 1 86 basel basel PROPN admet-144 1 87 , , PUNCT admet-144 1 88 switzerland switzerland PROPN admet-144 1 89 2 2 NUM admet-144 1 90 department department NOUN admet-144 1 91 of of ADP admet-144 1 92 pharmaceutical pharmaceutical NOUN admet-144 1 93 sciences science NOUN admet-144 1 94 , , PUNCT admet-144 1 95 division division NOUN admet-144 1 96 of of ADP admet-144 1 97 pharmaceutical pharmaceutical NOUN admet-144 1 98 technology technology NOUN admet-144 1 99 , , PUNCT admet-144 1 100 university university PROPN admet-144 1 101 of of ADP admet-144 1 102 basel basel PROPN admet-144 1 103 , , PUNCT admet-144 1 104 ch-4056 ch-4056 PROPN admet-144 1 105 basel basel PROPN admet-144 1 106 , , PUNCT admet-144 1 107 switzerland switzerland PROPN admet-144 1 108 * * PUNCT admet-144 1 109 corresponding correspond VERB admet-144 1 110 author author NOUN admet-144 1 111 : : PUNCT admet-144 1 112 e e NOUN admet-144 1 113 - - NOUN admet-144 1 114 mail mail NOUN admet-144 1 115 : : PUNCT admet-144 1 116 gian.camenisch@novartis.com gian.camenisch@novartis.com NOUN admet-144 1 117 ; ; PUNCT admet-144 1 118 tel tel PROPN admet-144 1 119 . . PUNCT admet-144 1 120 : : PUNCT admet-144 2 1 +41 +41 VERB admet-144 2 2 - - PUNCT admet-144 2 3 79 79 NUM admet-144 2 4 - - PUNCT admet-144 2 5 278 278 NUM admet-144 2 6 - - PUNCT admet-144 2 7 58 58 NUM admet-144 2 8 - - SYM admet-144 2 9 17 17 NUM admet-144 2 10 ; ; PUNCT admet-144 2 11 fax fax NOUN admet-144 2 12 : : PUNCT admet-144 2 13 +41 +41 PROPN admet-144 2 14 - - PUNCT admet-144 2 15 61 61 NUM admet-144 2 16 - - PUNCT admet-144 2 17 696 696 NUM admet-144 2 18 - - PUNCT admet-144 2 19 85 85 NUM admet-144 2 20 - - SYM admet-144 2 21 83 83 NUM admet-144 2 22 received receive VERB admet-144 2 23 : : PUNCT admet-144 2 24 november november PROPN admet-144 2 25 14 14 NUM admet-144 2 26 , , PUNCT admet-144 2 27 2014 2014 NUM admet-144 2 28 ; ; PUNCT admet-144 2 29 revised revise VERB admet-144 2 30 : : PUNCT admet-144 2 31 december december PROPN admet-144 2 32 18 18 NUM admet-144 2 33 , , PUNCT admet-144 2 34 2015 2015 NUM admet-144 2 35 ; ; PUNCT admet-144 2 36 published publish VERB admet-144 2 37 : : PUNCT admet-144 2 38 march march PROPN admet-144 2 39 31 31 NUM admet-144 2 40 , , PUNCT admet-144 2 41 2015 2015 NUM admet-144 2 42 abstract abstract ADJ admet-144 2 43 hepatic hepatic ADJ admet-144 2 44 elimination elimination NOUN admet-144 2 45 is be AUX admet-144 2 46 a a DET admet-144 2 47 function function NOUN admet-144 2 48 of of ADP admet-144 2 49 the the DET admet-144 2 50 interplay interplay NOUN admet-144 2 51 between between ADP admet-144 2 52 different different ADJ admet-144 2 53 processes process NOUN admet-144 2 54 such such ADJ admet-144 2 55 as as ADP admet-144 2 56 sinusoidal sinusoidal NOUN admet-144 2 57 uptake uptake NOUN admet-144 2 58 , , PUNCT admet-144 2 59 intracellular intracellular ADJ admet-144 2 60 metabolism metabolism NOUN admet-144 2 61 , , PUNCT admet-144 2 62 canalicular canalicular ADJ admet-144 2 63 ( ( PUNCT admet-144 2 64 biliary biliary NOUN admet-144 2 65 ) ) PUNCT admet-144 2 66 secretion secretion NOUN admet-144 2 67 , , PUNCT admet-144 2 68 and and CCONJ admet-144 2 69 sinusoidal sinusoidal NOUN admet-144 2 70 efflux efflux VERB admet-144 2 71 . . PUNCT admet-144 3 1 in in ADP admet-144 3 2 this this DET admet-144 3 3 review review NOUN admet-144 3 4 , , PUNCT admet-144 3 5 we we PRON admet-144 3 6 outline outline VERB admet-144 3 7 how how SCONJ admet-144 3 8 drugs drug NOUN admet-144 3 9 can can AUX admet-144 3 10 be be AUX admet-144 3 11 classified classify VERB admet-144 3 12 according accord VERB admet-144 3 13 to to ADP admet-144 3 14 their their PRON admet-144 3 15 in in X admet-144 3 16 vitro vitro X admet-144 3 17 determined determined ADJ admet-144 3 18 clearance clearance NOUN admet-144 3 19 mechanisms mechanism NOUN admet-144 3 20 using use VERB admet-144 3 21 the the DET admet-144 3 22 extended extended ADJ admet-144 3 23 clearance clearance NOUN admet-144 3 24 model model NOUN admet-144 3 25 as as ADP admet-144 3 26 a a DET admet-144 3 27 reference reference NOUN admet-144 3 28 . . PUNCT admet-144 4 1 the the DET admet-144 4 2 approach approach NOUN admet-144 4 3 enables enable VERB admet-144 4 4 the the DET admet-144 4 5 determination determination NOUN admet-144 4 6 of of ADP admet-144 4 7 the the DET admet-144 4 8 ratedetermining ratedetermine VERB admet-144 4 9 hepatic hepatic ADJ admet-144 4 10 clearance clearance NOUN admet-144 4 11 step step NOUN admet-144 4 12 . . PUNCT admet-144 5 1 some some DET admet-144 5 2 successful successful ADJ admet-144 5 3 applications application NOUN admet-144 5 4 will will AUX admet-144 5 5 be be AUX admet-144 5 6 highlighted highlight VERB admet-144 5 7 , , PUNCT admet-144 5 8 together together ADV admet-144 5 9 with with ADP admet-144 5 10 a a DET admet-144 5 11 discussion discussion NOUN admet-144 5 12 on on ADP admet-144 5 13 the the DET admet-144 5 14 major major ADJ admet-144 5 15 consequences consequence NOUN admet-144 5 16 for for ADP admet-144 5 17 the the DET admet-144 5 18 pharmacokinetics pharmacokinetic NOUN admet-144 5 19 and and CCONJ admet-144 5 20 the the DET admet-144 5 21 drug drug NOUN admet-144 5 22 - - PUNCT admet-144 5 23 drug drug NOUN admet-144 5 24 interaction interaction NOUN admet-144 5 25 potential potential NOUN admet-144 5 26 of of ADP admet-144 5 27 drugs drug NOUN admet-144 5 28 . . PUNCT admet-144 6 1 special special ADJ admet-144 6 2 emphasize emphasize NOUN admet-144 6 3 is be AUX admet-144 6 4 put put VERB admet-144 6 5 on on ADP admet-144 6 6 the the DET admet-144 6 7 role role NOUN admet-144 6 8 of of ADP admet-144 6 9 passive passive ADJ admet-144 6 10 permeability permeability NOUN admet-144 6 11 and and CCONJ admet-144 6 12 active active ADJ admet-144 6 13 transport transport NOUN admet-144 6 14 processes process NOUN admet-144 6 15 in in ADP admet-144 6 16 hepatic hepatic ADJ admet-144 6 17 elimination elimination NOUN admet-144 6 18 . . PUNCT admet-144 7 1 keywords keyword NOUN admet-144 7 2 extended extend VERB admet-144 7 3 clearance clearance NOUN admet-144 7 4 concept concept NOUN admet-144 7 5 classification classification NOUN admet-144 7 6 system system NOUN admet-144 7 7 ; ; PUNCT admet-144 7 8 hepatic hepatic ADJ admet-144 7 9 elimination elimination NOUN admet-144 7 10 ; ; PUNCT admet-144 7 11 passive passive ADJ admet-144 7 12 permeability permeability NOUN admet-144 7 13 ; ; PUNCT admet-144 7 14 transporters transporter NOUN admet-144 7 15 extended extend VERB admet-144 7 16 clearance clearance NOUN admet-144 7 17 model model NOUN admet-144 7 18 historically historically ADV admet-144 7 19 , , PUNCT admet-144 7 20 hepatic hepatic ADJ admet-144 7 21 clearance clearance NOUN admet-144 7 22 models model NOUN admet-144 7 23 assumed assume VERB admet-144 7 24 that that SCONJ admet-144 7 25 ( ( PUNCT admet-144 7 26 i i NOUN admet-144 7 27 ) ) PUNCT admet-144 7 28 the the DET admet-144 7 29 unbound unbound NOUN admet-144 7 30 drug drug NOUN admet-144 7 31 concentration concentration NOUN admet-144 7 32 in in ADP admet-144 7 33 blood blood NOUN admet-144 7 34 is be AUX admet-144 7 35 determining determine VERB admet-144 7 36 the the DET admet-144 7 37 hepatic hepatic ADJ admet-144 7 38 clearance clearance NOUN admet-144 7 39 ( ( PUNCT admet-144 7 40 metabolism metabolism NOUN admet-144 7 41 and/or and/or CCONJ admet-144 7 42 biliary biliary NOUN admet-144 7 43 excretion excretion NOUN admet-144 7 44 ) ) PUNCT admet-144 7 45 and and CCONJ admet-144 7 46 that that SCONJ admet-144 7 47 ( ( PUNCT admet-144 7 48 ii ii NOUN admet-144 7 49 ) ) PUNCT admet-144 7 50 there there PRON admet-144 7 51 is be VERB admet-144 7 52 no no DET admet-144 7 53 membrane membrane NOUN admet-144 7 54 transport transport NOUN admet-144 7 55 barrier barrier NOUN admet-144 7 56 limiting limit VERB admet-144 7 57 access access NOUN admet-144 7 58 to to ADP admet-144 7 59 the the DET admet-144 7 60 enzymes enzyme NOUN admet-144 7 61 or or CCONJ admet-144 7 62 transporters transporter NOUN admet-144 7 63 in in ADP admet-144 7 64 the the DET admet-144 7 65 hepatocyte hepatocyte NOUN admet-144 7 66 . . PUNCT admet-144 8 1 improved improve VERB admet-144 8 2 models model NOUN admet-144 8 3 , , PUNCT admet-144 8 4 however however ADV admet-144 8 5 , , PUNCT admet-144 8 6 reflect reflect VERB admet-144 8 7 the the DET admet-144 8 8 physiological physiological ADJ admet-144 8 9 reality reality NOUN admet-144 8 10 more more ADV admet-144 8 11 precisely precisely ADV admet-144 8 12 . . PUNCT admet-144 9 1 in in ADP admet-144 9 2 the the DET admet-144 9 3 liver liver NOUN admet-144 9 4 drugs drug NOUN admet-144 9 5 first first ADV admet-144 9 6 have have VERB admet-144 9 7 to to PART admet-144 9 8 overcome overcome VERB admet-144 9 9 the the DET admet-144 9 10 membrane membrane NOUN admet-144 9 11 barrier barrier NOUN admet-144 9 12 separating separate VERB admet-144 9 13 the the DET admet-144 9 14 blood blood NOUN admet-144 9 15 in in ADP admet-144 9 16 the the DET admet-144 9 17 sinusoid sinusoid NOUN admet-144 9 18 from from ADP admet-144 9 19 the the DET admet-144 9 20 cytosol cytosol NOUN admet-144 9 21 of of ADP admet-144 9 22 the the DET admet-144 9 23 hepatocytes hepatocytes PROPN admet-144 9 24 . . PUNCT admet-144 10 1 permeation permeation NOUN admet-144 10 2 across across ADP admet-144 10 3 this this DET admet-144 10 4 barrier barrier NOUN admet-144 10 5 might might AUX admet-144 10 6 occur occur VERB admet-144 10 7 by by ADP admet-144 10 8 passive passive ADJ admet-144 10 9 diffusion diffusion NOUN admet-144 10 10 and/or and/or CCONJ admet-144 10 11 active active ADJ admet-144 10 12 carrier carrier NOUN admet-144 10 13 - - PUNCT admet-144 10 14 mediated mediate VERB admet-144 10 15 transport transport NOUN admet-144 10 16 . . PUNCT admet-144 11 1 once once ADV admet-144 11 2 in in ADP admet-144 11 3 the the DET admet-144 11 4 cytosol cytosol NOUN admet-144 11 5 drugs drug NOUN admet-144 11 6 are be AUX admet-144 11 7 subject subject ADJ admet-144 11 8 to to ADP admet-144 11 9 metabolism metabolism NOUN admet-144 11 10 , , PUNCT admet-144 11 11 efflux efflux VERB admet-144 11 12 transporter transporter NOUN admet-144 11 13 - - PUNCT admet-144 11 14 mediated mediate VERB admet-144 11 15 canalicular canalicular NOUN admet-144 11 16 ( ( PUNCT admet-144 11 17 biliary biliary NOUN admet-144 11 18 ) ) PUNCT admet-144 11 19 secretion secretion NOUN admet-144 11 20 and/or and/or CCONJ admet-144 11 21 back back NOUN admet-144 11 22 - - PUNCT admet-144 11 23 flux flux NOUN admet-144 11 24 ( ( PUNCT admet-144 11 25 active active ADJ admet-144 11 26 or or CCONJ admet-144 11 27 passive passive ADJ admet-144 11 28 ) ) PUNCT admet-144 11 29 into into ADP admet-144 11 30 the the DET admet-144 11 31 sinusoid sinusoid NOUN admet-144 11 32 . . PUNCT admet-144 12 1 consequently consequently ADV admet-144 12 2 , , PUNCT admet-144 12 3 generally generally ADV admet-144 12 4 referred refer VERB admet-144 12 5 as as ADP admet-144 12 6 the the DET admet-144 12 7 extended extended ADJ admet-144 12 8 clearance clearance NOUN admet-144 12 9 model model NOUN admet-144 12 10 ( ( PUNCT admet-144 12 11 ecm ecm PROPN admet-144 12 12 ) ) PUNCT admet-144 12 13 , , PUNCT admet-144 12 14 the the DET admet-144 12 15 overall overall ADJ admet-144 12 16 hepatic hepatic ADJ admet-144 12 17 intrinsic intrinsic ADJ admet-144 12 18 drug drug NOUN admet-144 12 19 clearance clearance NOUN admet-144 12 20 ( ( PUNCT admet-144 12 21 clh clh NOUN admet-144 12 22 , , PUNCT admet-144 12 23 int int NOUN admet-144 12 24 ) ) PUNCT admet-144 12 25 can can AUX admet-144 12 26 be be AUX admet-144 12 27 described describe VERB admet-144 12 28 as as ADP admet-144 12 29 the the DET admet-144 12 30 interplay interplay NOUN admet-144 12 31 between between ADP admet-144 12 32 all all DET admet-144 12 33 these these DET admet-144 12 34 processes process NOUN admet-144 12 35 as as SCONJ admet-144 12 36 follows follow VERB admet-144 12 37 [ [ X admet-144 12 38 1,2 1,2 NUM admet-144 12 39 ] ] PUNCT admet-144 12 40 : : PUNCT admet-144 12 41 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 12 42 , , PUNCT admet-144 12 43 𝑖𝑛𝑑 𝑖𝑛𝑑 PROPN admet-144 13 1 = = PUNCT admet-144 13 2 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 13 3 βˆ™ βˆ™ NOUN admet-144 13 4 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 13 5 𝑃𝑆𝑒𝑓𝑓 𝑃𝑆𝑒𝑓𝑓 PROPN admet-144 13 6 + + NUM admet-144 13 7 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 13 8 = = SYM admet-144 13 9 ( ( PUNCT admet-144 13 10 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 13 11 , , PUNCT admet-144 13 12 π‘Žπ‘π‘‘ π‘Žπ‘π‘‘ PROPN admet-144 13 13 + + CCONJ admet-144 13 14 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 13 15 , , PUNCT admet-144 13 16 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 13 17 ) ) PUNCT admet-144 14 1 βˆ™ βˆ™ PROPN admet-144 14 2 ( ( PUNCT admet-144 14 3 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 14 4 , , PUNCT admet-144 14 5 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ NOUN admet-144 14 6 + + CCONJ admet-144 14 7 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 14 8 , , PUNCT admet-144 14 9 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 14 10 ) ) PUNCT admet-144 14 11 𝑃𝑆𝑒𝑓𝑓 𝑃𝑆𝑒𝑓𝑓 PROPN admet-144 14 12 , , PUNCT admet-144 14 13 π‘Žπ‘π‘‘ π‘Žπ‘π‘‘ NOUN admet-144 14 14 + + CCONJ admet-144 14 15 𝑃𝑆𝑒𝑓𝑓 𝑃𝑆𝑒𝑓𝑓 PROPN admet-144 14 16 , , PUNCT admet-144 14 17 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 14 18 + + CCONJ admet-144 14 19 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 14 20 , , PUNCT admet-144 14 21 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ NOUN admet-144 14 22 + + CCONJ admet-144 14 23 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 14 24 , , PUNCT admet-144 14 25 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 14 26 ( ( PUNCT admet-144 14 27 1 1 NUM admet-144 14 28 ) ) PUNCT admet-144 14 29 http://www.pub.iapchem.org/ojs/index.php/admet/index http://www.pub.iapchem.org/ojs/index.php/admet/index NOUN admet-144 14 30 mailto:gian.camenisch@novartis.com mailto:gian.camenisch@novartis.com PROPN admet-144 15 1 camenisch camenisch PROPN admet-144 15 2 et et PROPN admet-144 15 3 al al PROPN admet-144 15 4 . . PROPN admet-144 15 5 admet admet PROPN admet-144 15 6 & & CCONJ admet-144 15 7 dmpk dmpk PROPN admet-144 15 8 3(1 3(1 NUM admet-144 15 9 ) ) PUNCT admet-144 15 10 ( ( PUNCT admet-144 15 11 2015 2015 NUM admet-144 15 12 ) ) PUNCT admet-144 15 13 1 1 NUM admet-144 15 14 - - SYM admet-144 15 15 14 14 NUM admet-144 15 16 2 2 NUM admet-144 15 17 where where SCONJ admet-144 15 18 , , PUNCT admet-144 15 19 psinf psinf ADJ admet-144 15 20 , , PUNCT admet-144 15 21 act act NOUN admet-144 15 22 and and CCONJ admet-144 15 23 psinf psinf ADJ admet-144 15 24 , , PUNCT admet-144 15 25 pas pa NOUN admet-144 15 26 are be AUX admet-144 15 27 the the DET admet-144 15 28 active active ADJ admet-144 15 29 and and CCONJ admet-144 15 30 passive passive ADJ admet-144 15 31 hepatic hepatic ADJ admet-144 15 32 influx influx NOUN admet-144 15 33 clearances clearance NOUN admet-144 15 34 from from ADP admet-144 15 35 the the DET admet-144 15 36 blood blood NOUN admet-144 15 37 , , PUNCT admet-144 15 38 respectively respectively ADV admet-144 15 39 , , PUNCT admet-144 15 40 clint clint NOUN admet-144 15 41 , , PUNCT admet-144 15 42 sec sec PROPN admet-144 15 43 is be AUX admet-144 15 44 the the DET admet-144 15 45 intrinsic intrinsic ADJ admet-144 15 46 biliary biliary ADJ admet-144 15 47 secretion secretion NOUN admet-144 15 48 clearance clearance NOUN admet-144 15 49 , , PUNCT admet-144 15 50 and and CCONJ admet-144 15 51 clint clint NOUN admet-144 15 52 , , PUNCT admet-144 15 53 met meet VERB admet-144 15 54 is be AUX admet-144 15 55 the the DET admet-144 15 56 intrinsic intrinsic ADJ admet-144 15 57 metabolic metabolic NOUN admet-144 15 58 clearance clearance NOUN admet-144 15 59 . . PUNCT admet-144 16 1 pseff pseff NOUN admet-144 16 2 , , PUNCT admet-144 16 3 act act NOUN admet-144 16 4 and and CCONJ admet-144 16 5 pseff pseff NOUN admet-144 16 6 , , PUNCT admet-144 16 7 pas pas PROPN admet-144 16 8 describe describe VERB admet-144 16 9 the the DET admet-144 16 10 active active ADJ admet-144 16 11 and and CCONJ admet-144 16 12 passive passive ADJ admet-144 16 13 sinusoidal sinusoidal NOUN admet-144 16 14 efflux efflux VERB admet-144 16 15 from from ADP admet-144 16 16 the the DET admet-144 16 17 hepatocytes hepatocyte NOUN admet-144 16 18 back back ADV admet-144 16 19 into into ADP admet-144 16 20 the the DET admet-144 16 21 blood blood NOUN admet-144 16 22 , , PUNCT admet-144 16 23 respectively respectively ADV admet-144 16 24 . . PUNCT admet-144 17 1 psinf psinf NOUN admet-144 17 2 is be AUX admet-144 17 3 the the DET admet-144 17 4 sum sum NOUN admet-144 17 5 of of ADP admet-144 17 6 psinf psinf ADJ admet-144 17 7 , , PUNCT admet-144 17 8 act act NOUN admet-144 17 9 and and CCONJ admet-144 17 10 psinf psinf ADJ admet-144 17 11 , , PUNCT admet-144 17 12 pas pas NOUN admet-144 17 13 , , PUNCT admet-144 17 14 pseff pseff NOUN admet-144 17 15 is be AUX admet-144 17 16 the the DET admet-144 17 17 sum sum NOUN admet-144 17 18 of of ADP admet-144 17 19 pseff pseff NOUN admet-144 17 20 , , PUNCT admet-144 17 21 act act NOUN admet-144 17 22 and and CCONJ admet-144 17 23 pseff pseff NOUN admet-144 17 24 , , PUNCT admet-144 17 25 pas pas PROPN admet-144 17 26 , , PUNCT admet-144 17 27 clint clint NOUN admet-144 17 28 is be AUX admet-144 17 29 the the DET admet-144 17 30 sum sum NOUN admet-144 17 31 of of ADP admet-144 17 32 clint clint NOUN admet-144 17 33 , , PUNCT admet-144 17 34 sec sec PROPN admet-144 17 35 and and CCONJ admet-144 17 36 clint clint NOUN admet-144 17 37 , , PUNCT admet-144 17 38 met meet VERB admet-144 17 39 and and CCONJ admet-144 17 40 clint clint NOUN admet-144 17 41 , , PUNCT admet-144 17 42 h h PROPN admet-144 17 43 is be AUX admet-144 17 44 the the DET admet-144 17 45 overall overall ADJ admet-144 17 46 intrinsic intrinsic ADJ admet-144 17 47 hepatic hepatic ADJ admet-144 17 48 clearance clearance NOUN admet-144 17 49 . . PUNCT admet-144 18 1 the the DET admet-144 18 2 extended extended ADJ admet-144 18 3 clearance clearance NOUN admet-144 18 4 model model NOUN admet-144 18 5 allows allow VERB admet-144 18 6 the the DET admet-144 18 7 identification identification NOUN admet-144 18 8 of of ADP admet-144 18 9 the the DET admet-144 18 10 rate rate NOUN admet-144 18 11 - - PUNCT admet-144 18 12 determining determine VERB admet-144 18 13 hepatic hepatic ADJ admet-144 18 14 clearance clearance NOUN admet-144 18 15 step step NOUN admet-144 18 16 for for ADP admet-144 18 17 a a DET admet-144 18 18 given give VERB admet-144 18 19 drug drug NOUN admet-144 18 20 molecule molecule NOUN admet-144 18 21 [ [ X admet-144 18 22 1 1 NUM admet-144 18 23 ] ] PUNCT admet-144 18 24 . . PUNCT admet-144 19 1 depending depend VERB admet-144 19 2 on on ADP admet-144 19 3 the the DET admet-144 19 4 relative relative ADJ admet-144 19 5 contributions contribution NOUN admet-144 19 6 of of ADP admet-144 19 7 the the DET admet-144 19 8 individual individual ADJ admet-144 19 9 processes process NOUN admet-144 19 10 in in ADP admet-144 19 11 eq eq ADP admet-144 19 12 . . PUNCT admet-144 20 1 ( ( PUNCT admet-144 20 2 1 1 NUM admet-144 20 3 ) ) PUNCT admet-144 20 4 , , PUNCT admet-144 20 5 four four NUM admet-144 20 6 different different ADJ admet-144 20 7 cases case NOUN admet-144 20 8 can can AUX admet-144 20 9 be be AUX admet-144 20 10 distinguished distinguish VERB admet-144 20 11 ( ( PUNCT admet-144 20 12 fig fig NOUN admet-144 20 13 . . PUNCT admet-144 21 1 1 1 NUM admet-144 21 2 ) ) PUNCT admet-144 21 3 . . PUNCT admet-144 22 1 while while SCONJ admet-144 22 2 ( ( PUNCT admet-144 22 3 passive passive ADJ admet-144 22 4 ) ) PUNCT admet-144 22 5 hepatic hepatic ADJ admet-144 22 6 uptake uptake NOUN admet-144 22 7 is be AUX admet-144 22 8 the the DET admet-144 22 9 rate rate NOUN admet-144 22 10 - - PUNCT admet-144 22 11 determining determine VERB admet-144 22 12 step step NOUN admet-144 22 13 for for ADP admet-144 22 14 ecm ecm PROPN admet-144 22 15 class class NOUN admet-144 22 16 1 1 NUM admet-144 22 17 compounds compound NOUN admet-144 22 18 , , PUNCT admet-144 22 19 the the DET admet-144 22 20 sum sum NOUN admet-144 22 21 of of ADP admet-144 22 22 metabolism metabolism NOUN admet-144 22 23 and and CCONJ admet-144 22 24 efflux efflux VERB admet-144 22 25 transporter transporter NOUN admet-144 22 26 - - PUNCT admet-144 22 27 mediated mediate VERB admet-144 22 28 biliary biliary ADJ admet-144 22 29 elimination elimination NOUN admet-144 22 30 is be AUX admet-144 22 31 predicted predict VERB admet-144 22 32 to to PART admet-144 22 33 be be AUX admet-144 22 34 the the DET admet-144 22 35 rate rate NOUN admet-144 22 36 - - PUNCT admet-144 22 37 limiting limit VERB admet-144 22 38 step step NOUN admet-144 22 39 for for ADP admet-144 22 40 ecm ecm NOUN admet-144 22 41 class class NOUN admet-144 22 42 2 2 NUM admet-144 22 43 compounds compound NOUN admet-144 22 44 . . PUNCT admet-144 23 1 the the DET admet-144 23 2 overall overall ADJ admet-144 23 3 hepatic hepatic ADJ admet-144 23 4 uptake uptake NOUN admet-144 23 5 ( ( PUNCT admet-144 23 6 sum sum NOUN admet-144 23 7 of of ADP admet-144 23 8 active active ADJ admet-144 23 9 and and CCONJ admet-144 23 10 passive passive ADJ admet-144 23 11 ) ) PUNCT admet-144 23 12 is be AUX admet-144 23 13 projected project VERB admet-144 23 14 to to PART admet-144 23 15 be be AUX admet-144 23 16 rate rate NOUN admet-144 23 17 - - PUNCT admet-144 23 18 determining determine VERB admet-144 23 19 for for ADP admet-144 23 20 ecm ecm NOUN admet-144 23 21 class class NOUN admet-144 23 22 3 3 NUM admet-144 23 23 compounds compound NOUN admet-144 23 24 , , PUNCT admet-144 23 25 whereas whereas SCONJ admet-144 23 26 the the DET admet-144 23 27 overall overall ADJ admet-144 23 28 intrinsic intrinsic ADJ admet-144 23 29 clearance clearance NOUN admet-144 23 30 of of ADP admet-144 23 31 ecm ecm PROPN admet-144 23 32 class class NOUN admet-144 23 33 4 4 NUM admet-144 23 34 compounds compound NOUN admet-144 23 35 is be AUX admet-144 23 36 dependent dependent ADJ admet-144 23 37 on on ADP admet-144 23 38 the the DET admet-144 23 39 interplay interplay NOUN admet-144 23 40 of of ADP admet-144 23 41 all all DET admet-144 23 42 processes process NOUN admet-144 23 43 involved involve VERB admet-144 23 44 in in ADP admet-144 23 45 hepatic hepatic ADJ admet-144 23 46 elimination elimination NOUN admet-144 23 47 ( ( PUNCT admet-144 23 48 namely namely ADV admet-144 23 49 metabolism metabolism NOUN admet-144 23 50 , , PUNCT admet-144 23 51 uptake uptake ADJ admet-144 23 52 , , PUNCT admet-144 23 53 and and CCONJ admet-144 23 54 efflux efflux VERB admet-144 23 55 ) ) PUNCT admet-144 23 56 . . PUNCT admet-144 24 1 figure figure VERB admet-144 24 2 1 1 NUM admet-144 24 3 . . PUNCT admet-144 24 4 rate rate NOUN admet-144 24 5 - - PUNCT admet-144 24 6 determining determine VERB admet-144 24 7 hepatic hepatic ADJ admet-144 24 8 clearance clearance NOUN admet-144 24 9 processes process NOUN admet-144 24 10 ( ( PUNCT admet-144 24 11 inner inner ADJ admet-144 24 12 panels panel NOUN admet-144 24 13 ) ) PUNCT admet-144 24 14 derived derive VERB admet-144 24 15 from from ADP admet-144 24 16 the the DET admet-144 24 17 extended extended ADJ admet-144 24 18 clearance clearance NOUN admet-144 24 19 model model NOUN admet-144 24 20 ( ( PUNCT admet-144 24 21 ecm ecm PROPN admet-144 24 22 ) ) PUNCT admet-144 24 23 based base VERB admet-144 24 24 on on ADP admet-144 24 25 different different ADJ admet-144 24 26 pre pre NOUN admet-144 24 27 - - NOUN admet-144 24 28 requisites requisite NOUN admet-144 24 29 ( ( PUNCT admet-144 24 30 outer outer ADJ admet-144 24 31 panels panel NOUN admet-144 24 32 ) ) PUNCT admet-144 24 33 and and CCONJ admet-144 24 34 the the DET admet-144 24 35 assumption assumption NOUN admet-144 24 36 thyat thyat PROPN admet-144 24 37 pseff pseff PROPN admet-144 24 38 , , PUNCT admet-144 24 39 pas pas PROPN admet-144 24 40 is be AUX admet-144 24 41 equal equal ADJ admet-144 24 42 to to PART admet-144 24 43 psinf psinf VERB admet-144 24 44 , , PUNCT admet-144 24 45 pas pas NOUN admet-144 24 46 and and CCONJ admet-144 24 47 that that DET admet-144 24 48 pseff pseff NOUN admet-144 24 49 , , PUNCT admet-144 24 50 act act NOUN admet-144 24 51 equals equal VERB admet-144 24 52 zero zero NUM admet-144 24 53 ( ( PUNCT admet-144 24 54 eq eq NOUN admet-144 24 55 . . PUNCT admet-144 24 56 ( ( PUNCT admet-144 24 57 1 1 NUM admet-144 24 58 ) ) PUNCT admet-144 24 59 ) ) PUNCT admet-144 24 60 . . PUNCT admet-144 25 1 viewing view VERB admet-144 25 2 the the DET admet-144 25 3 liver liver NOUN admet-144 25 4 as as ADP admet-144 25 5 a a DET admet-144 25 6 single single ADJ admet-144 25 7 compartment compartment NOUN admet-144 25 8 and and CCONJ admet-144 25 9 assuming assume VERB admet-144 25 10 that that SCONJ admet-144 25 11 drug drug NOUN admet-144 25 12 molecules molecule NOUN admet-144 25 13 are be AUX admet-144 25 14 distributing distribute VERB admet-144 25 15 instantaneously instantaneously ADV admet-144 25 16 and and CCONJ admet-144 25 17 homogeneously homogeneously ADV admet-144 25 18 within within ADP admet-144 25 19 the the DET admet-144 25 20 liver liver NOUN admet-144 25 21 upon upon SCONJ admet-144 25 22 entering enter VERB admet-144 25 23 ( ( PUNCT admet-144 25 24 well well ADV admet-144 25 25 - - PUNCT admet-144 25 26 stirred stir VERB admet-144 25 27 liver liver NOUN admet-144 25 28 model model NOUN admet-144 25 29 ) ) PUNCT admet-144 25 30 the the DET admet-144 25 31 hepatic hepatic ADJ admet-144 25 32 blood blood NOUN admet-144 25 33 clearance clearance NOUN admet-144 25 34 ( ( PUNCT admet-144 25 35 clh clh NOUN admet-144 25 36 ) ) PUNCT admet-144 25 37 can can AUX admet-144 25 38 be be AUX admet-144 25 39 calculated calculate VERB admet-144 25 40 with with ADP admet-144 25 41 : : PUNCT admet-144 25 42 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 25 43 = = PUNCT admet-144 26 1 π‘„β„Ž π‘„β„Ž PROPN admet-144 26 2 βˆ™ βˆ™ PROPN admet-144 26 3 𝑓𝑒 𝑓𝑒 INTJ admet-144 26 4 , , PUNCT admet-144 26 5 𝑏 𝑏 PROPN admet-144 26 6 βˆ™ βˆ™ PROPN admet-144 26 7 ( ( PUNCT admet-144 26 8 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 26 9 , , PUNCT admet-144 26 10 π‘Žπ‘π‘‘ π‘Žπ‘π‘‘ PROPN admet-144 26 11 + + CCONJ admet-144 26 12 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 26 13 , , PUNCT admet-144 26 14 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 26 15 ) ) PUNCT admet-144 27 1 βˆ™ βˆ™ PROPN admet-144 27 2 ( ( PUNCT admet-144 27 3 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 27 4 , , PUNCT admet-144 27 5 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ NOUN admet-144 27 6 + + CCONJ admet-144 27 7 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 27 8 , , PUNCT admet-144 27 9 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 27 10 ) ) PUNCT admet-144 28 1 π‘„β„Ž π‘„β„Ž PROPN admet-144 28 2 βˆ™ βˆ™ PROPN admet-144 28 3 ( ( PUNCT admet-144 28 4 𝑃𝑆𝑒𝑓𝑓 𝑃𝑆𝑒𝑓𝑓 PROPN admet-144 28 5 , , PUNCT admet-144 28 6 π‘Žπ‘π‘‘ π‘Žπ‘π‘‘ NOUN admet-144 28 7 + + CCONJ admet-144 28 8 𝑃𝑆𝑒𝑓𝑓 𝑃𝑆𝑒𝑓𝑓 PROPN admet-144 28 9 , , PUNCT admet-144 28 10 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 28 11 + + CCONJ admet-144 28 12 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 28 13 , , PUNCT admet-144 28 14 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ NOUN admet-144 28 15 + + CCONJ admet-144 28 16 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 28 17 , , PUNCT admet-144 28 18 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 28 19 ) ) PUNCT admet-144 28 20 + + NUM admet-144 28 21 𝑓𝑒 𝑓𝑒 NOUN admet-144 28 22 , , PUNCT admet-144 28 23 𝑏 𝑏 PROPN admet-144 28 24 βˆ™ βˆ™ PROPN admet-144 28 25 ( ( PUNCT admet-144 28 26 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 28 27 , , PUNCT admet-144 28 28 π‘Žπ‘π‘‘ π‘Žπ‘π‘‘ PROPN admet-144 28 29 + + CCONJ admet-144 28 30 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 28 31 , , PUNCT admet-144 28 32 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 28 33 ) ) PUNCT admet-144 28 34 βˆ™ βˆ™ PROPN admet-144 28 35 ( ( PUNCT admet-144 28 36 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 28 37 , , PUNCT admet-144 28 38 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ NOUN admet-144 28 39 + + CCONJ admet-144 28 40 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 28 41 , , PUNCT admet-144 28 42 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 28 43 ) ) PUNCT admet-144 28 44 ( ( PUNCT admet-144 28 45 2 2 X admet-144 28 46 ) ) PUNCT admet-144 28 47 admet admet PROPN admet-144 28 48 & & CCONJ admet-144 28 49 dmpk dmpk PROPN admet-144 28 50 3(1 3(1 NUM admet-144 28 51 ) ) PUNCT admet-144 28 52 ( ( PUNCT admet-144 28 53 2015 2015 NUM admet-144 28 54 ) ) PUNCT admet-144 28 55 1 1 NUM admet-144 28 56 - - SYM admet-144 28 57 14 14 NUM admet-144 28 58 extended extended ADJ admet-144 28 59 clearance clearance NOUN admet-144 28 60 concept concept NOUN admet-144 28 61 classification classification NOUN admet-144 28 62 system system NOUN admet-144 28 63 ( ( PUNCT admet-144 28 64 ecccs ecccs NOUN admet-144 28 65 ) ) PUNCT admet-144 28 66 doi doi NOUN admet-144 28 67 : : PUNCT admet-144 28 68 10.5599 10.5599 NUM admet-144 28 69 / / SYM admet-144 28 70 admet.3.1.144 admet.3.1.144 PROPN admet-144 28 71 3 3 NUM admet-144 28 72 where where SCONJ admet-144 28 73 qh qh NOUN admet-144 28 74 is be AUX admet-144 28 75 the the DET admet-144 28 76 hepatic hepatic ADJ admet-144 28 77 blood blood NOUN admet-144 28 78 flow flow NOUN admet-144 28 79 ( ( PUNCT admet-144 28 80 20.7 20.7 NUM admet-144 28 81 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 28 82 ) ) PUNCT admet-144 28 83 ) ) PUNCT admet-144 28 84 and and CCONJ admet-144 28 85 fu fu PROPN admet-144 28 86 , , PUNCT admet-144 28 87 b b PROPN admet-144 28 88 is be AUX admet-144 28 89 the the DET admet-144 28 90 unbound unbound NOUN admet-144 28 91 fraction fraction NOUN admet-144 28 92 in in ADP admet-144 28 93 blood blood NOUN admet-144 28 94 . . PUNCT admet-144 29 1 the the DET admet-144 29 2 clearance clearance NOUN admet-144 29 3 parameters parameter NOUN admet-144 29 4 of of ADP admet-144 29 5 the the DET admet-144 29 6 extended extended ADJ admet-144 29 7 clearance clearance NOUN admet-144 29 8 model model NOUN admet-144 29 9 can can AUX admet-144 29 10 be be AUX admet-144 29 11 determined determine VERB admet-144 29 12 experimentally experimentally ADV admet-144 29 13 as as SCONJ admet-144 29 14 discussed discuss VERB admet-144 29 15 in in ADP admet-144 29 16 full full ADJ admet-144 29 17 detail detail NOUN admet-144 29 18 elsewhere elsewhere ADV admet-144 29 19 [ [ X admet-144 29 20 1,3 1,3 NUM admet-144 29 21 ] ] PUNCT admet-144 29 22 . . PUNCT admet-144 30 1 in in ADP admet-144 30 2 brief brief ADJ admet-144 30 3 , , PUNCT admet-144 30 4 psinf psinf ADJ admet-144 30 5 , , PUNCT admet-144 30 6 act act NOUN admet-144 30 7 and and CCONJ admet-144 30 8 psinf psinf VERB admet-144 30 9 , , PUNCT admet-144 30 10 pas pas PROPN admet-144 30 11 can can AUX admet-144 30 12 be be AUX admet-144 30 13 assessed assess VERB admet-144 30 14 by by ADP admet-144 30 15 uptake uptake ADJ admet-144 30 16 experiments experiment NOUN admet-144 30 17 in in ADP admet-144 30 18 suspended suspend VERB admet-144 30 19 human human ADJ admet-144 30 20 hepatocytes hepatocyte NOUN admet-144 30 21 ( ( PUNCT admet-144 30 22 shh shh NOUN admet-144 30 23 ) ) PUNCT admet-144 30 24 , , PUNCT admet-144 30 25 clint clint NOUN admet-144 30 26 , , PUNCT admet-144 30 27 sec sec PROPN admet-144 30 28 can can AUX admet-144 30 29 be be AUX admet-144 30 30 determined determine VERB admet-144 30 31 in in ADP admet-144 30 32 human human ADJ admet-144 30 33 sandwich sandwich NOUN admet-144 30 34 - - PUNCT admet-144 30 35 cultured cultured ADJ admet-144 30 36 hepatocyte hepatocyte NOUN admet-144 30 37 incubations incubation NOUN admet-144 30 38 ( ( PUNCT admet-144 30 39 generally generally ADV admet-144 30 40 assuming assume VERB admet-144 30 41 that that SCONJ admet-144 30 42 metabolism metabolism NOUN admet-144 30 43 in in ADP admet-144 30 44 this this DET admet-144 30 45 system system NOUN admet-144 30 46 is be AUX admet-144 30 47 negligible negligible ADJ admet-144 30 48 ) ) PUNCT admet-144 30 49 whereas whereas SCONJ admet-144 30 50 clint clint NOUN admet-144 30 51 , , PUNCT admet-144 30 52 met meet VERB admet-144 30 53 , , PUNCT admet-144 30 54 assuming assume VERB admet-144 30 55 absence absence NOUN admet-144 30 56 of of ADP admet-144 30 57 non non ADJ admet-144 30 58 - - ADJ admet-144 30 59 oxidative oxidative ADJ admet-144 30 60 metabolism metabolism NOUN admet-144 30 61 , , PUNCT admet-144 30 62 is be AUX admet-144 30 63 usually usually ADV admet-144 30 64 experimentally experimentally ADV admet-144 30 65 evaluated evaluate VERB admet-144 30 66 in in ADP admet-144 30 67 human human ADJ admet-144 30 68 liver liver NOUN admet-144 30 69 microsomal microsomal NOUN admet-144 30 70 ( ( PUNCT admet-144 30 71 hlm hlm ADJ admet-144 30 72 ) ) PUNCT admet-144 30 73 incubations incubation NOUN admet-144 30 74 . . PUNCT admet-144 31 1 efflux efflux VERB admet-144 31 2 over over ADP admet-144 31 3 the the DET admet-144 31 4 sinusoidal sinusoidal ADJ admet-144 31 5 membrane membrane NOUN admet-144 31 6 from from ADP admet-144 31 7 hepatocytes hepatocyte NOUN admet-144 31 8 back back ADV admet-144 31 9 into into ADP admet-144 31 10 the the DET admet-144 31 11 blood blood NOUN admet-144 31 12 is be AUX admet-144 31 13 frequently frequently ADV admet-144 31 14 assumed assume VERB admet-144 31 15 to to PART admet-144 31 16 occur occur VERB admet-144 31 17 via via ADP admet-144 31 18 passive passive ADJ admet-144 31 19 diffusion diffusion NOUN admet-144 31 20 only only ADV admet-144 31 21 ( ( PUNCT admet-144 31 22 i.e. i.e. X admet-144 31 23 pseff pseff NOUN admet-144 31 24 , , PUNCT admet-144 31 25 act act NOUN admet-144 31 26 = = SYM admet-144 31 27 0 0 NUM admet-144 31 28 ) ) PUNCT admet-144 31 29 . . PUNCT admet-144 32 1 the the DET admet-144 32 2 experimental experimental ADJ admet-144 32 3 determination determination NOUN admet-144 32 4 of of ADP admet-144 32 5 this this DET admet-144 32 6 parameter parameter NOUN admet-144 32 7 is be AUX admet-144 32 8 difficult difficult ADJ admet-144 32 9 . . PUNCT admet-144 33 1 in in ADP admet-144 33 2 the the DET admet-144 33 3 absence absence NOUN admet-144 33 4 of of ADP admet-144 33 5 measured measured ADJ admet-144 33 6 data datum NOUN admet-144 33 7 , , PUNCT admet-144 33 8 the the DET admet-144 33 9 passive passive ADJ admet-144 33 10 sinusoidal sinusoidal NOUN admet-144 33 11 efflux efflux NOUN admet-144 33 12 is be AUX admet-144 33 13 usually usually ADV admet-144 33 14 assumed assume VERB admet-144 33 15 to to PART admet-144 33 16 be be AUX admet-144 33 17 equal equal ADJ admet-144 33 18 to to ADP admet-144 33 19 the the DET admet-144 33 20 passive passive ADJ admet-144 33 21 influx influx NOUN admet-144 33 22 ( ( PUNCT admet-144 33 23 i.e. i.e. X admet-144 33 24 pseff pseff NOUN admet-144 33 25 , , PUNCT admet-144 33 26 pas pas NOUN admet-144 33 27 = = SYM admet-144 33 28 psinf psinf ADJ admet-144 33 29 , , PUNCT admet-144 33 30 pas pas PROPN admet-144 33 31 ) ) PUNCT admet-144 33 32 . . PUNCT admet-144 34 1 the the DET admet-144 34 2 individual individual ADJ admet-144 34 3 clearances clearance NOUN admet-144 34 4 can can AUX admet-144 34 5 finally finally ADV admet-144 34 6 be be AUX admet-144 34 7 fed feed VERB admet-144 34 8 into into ADP admet-144 34 9 eq eq NOUN admet-144 34 10 . . PUNCT admet-144 35 1 ( ( PUNCT admet-144 35 2 1 1 NUM admet-144 35 3 ) ) PUNCT admet-144 35 4 and and CCONJ admet-144 35 5 eq eq NOUN admet-144 35 6 . . PUNCT admet-144 36 1 ( ( PUNCT admet-144 36 2 2 2 NUM admet-144 36 3 ) ) PUNCT admet-144 36 4 to to PART admet-144 36 5 predict predict VERB admet-144 36 6 clh clh NOUN admet-144 36 7 , , PUNCT admet-144 36 8 int int NOUN admet-144 36 9 and and CCONJ admet-144 36 10 clh clh NOUN admet-144 36 11 of of ADP admet-144 36 12 a a DET admet-144 36 13 drug drug NOUN admet-144 36 14 . . PUNCT admet-144 37 1 table table NOUN admet-144 37 2 1 1 NUM admet-144 37 3 provides provide VERB admet-144 37 4 a a DET admet-144 37 5 compilation compilation NOUN admet-144 37 6 of of ADP admet-144 37 7 experimentally experimentally ADV admet-144 37 8 determined determine VERB admet-144 37 9 intrinsic intrinsic ADJ admet-144 37 10 clearances clearance NOUN admet-144 37 11 for for ADP admet-144 37 12 a a DET admet-144 37 13 dataset dataset NOUN admet-144 37 14 of of ADP admet-144 37 15 19 19 NUM admet-144 37 16 physicochemically physicochemically ADV admet-144 37 17 diverse diverse ADJ admet-144 37 18 compounds compound NOUN admet-144 37 19 from from ADP admet-144 37 20 the the DET admet-144 37 21 literature literature NOUN admet-144 37 22 together together ADV admet-144 37 23 with with ADP admet-144 37 24 corresponding correspond VERB admet-144 37 25 in in ADP admet-144 37 26 vivo vivo NOUN admet-144 37 27 reference reference NOUN admet-144 37 28 data datum NOUN admet-144 37 29 and and CCONJ admet-144 37 30 the the DET admet-144 37 31 ecm ecm PROPN admet-144 37 32 classification classification NOUN admet-144 37 33 according accord VERB admet-144 37 34 to to ADP admet-144 37 35 fig fig NOUN admet-144 37 36 . . PUNCT admet-144 38 1 1 1 NUM admet-144 39 1 [ [ SYM admet-144 39 2 1 1 NUM admet-144 39 3 , , PUNCT admet-144 39 4 4 4 NUM admet-144 39 5 - - SYM admet-144 39 6 7 7 NUM admet-144 39 7 ] ] PUNCT admet-144 39 8 . . PUNCT admet-144 40 1 table table NOUN admet-144 40 2 1 1 NUM admet-144 40 3 . . PUNCT admet-144 41 1 experimental experimental ADJ admet-144 41 2 human human PROPN admet-144 41 3 hepatic hepatic ADJ admet-144 41 4 process process NOUN admet-144 41 5 clearances clearance NOUN admet-144 41 6 from from ADP admet-144 41 7 in in ADP admet-144 41 8 vitro vitro X admet-144 41 9 assays assay NOUN admet-144 41 10 and and CCONJ admet-144 41 11 corresponding correspond VERB admet-144 41 12 in in ADP admet-144 41 13 vivo vivo NOUN admet-144 41 14 reference reference NOUN admet-144 41 15 data datum NOUN admet-144 41 16 . . PUNCT admet-144 42 1 experimental experimental ADJ admet-144 42 2 in in ADP admet-144 42 3 vitro vitro X admet-144 42 4 data datum NOUN admet-144 42 5 in in ADP admet-144 42 6 vivo vivo NOUN admet-144 42 7 reference reference NOUN admet-144 42 8 data datum NOUN admet-144 42 9 compounds compound VERB admet-144 42 10 ecm ecm PROPN admet-144 42 11 / / SYM admet-144 42 12 ecc ecc PROPN admet-144 42 13 psinf psinf NOUN admet-144 42 14 , , PUNCT admet-144 42 15 act act NOUN admet-144 42 16 pseff pseff NOUN admet-144 42 17 = = SYM admet-144 42 18 psinf psinf NOUN admet-144 42 19 , , PUNCT admet-144 42 20 pas pas PROPN admet-144 42 21 clint clint NOUN admet-144 42 22 , , PUNCT admet-144 42 23 met meet VERB admet-144 42 24 , , PUNCT admet-144 42 25 hlm hlm PROPN admet-144 42 26 clint clint NOUN admet-144 42 27 , , PUNCT admet-144 42 28 met meet VERB admet-144 42 29 , , PUNCT admet-144 42 30 hh hh PROPN admet-144 42 31 clint clint PROPN admet-144 42 32 , , PUNCT admet-144 42 33 sec sec PROPN admet-144 42 34 fu fu PROPN admet-144 42 35 , , PUNCT admet-144 42 36 b b PROPN admet-144 42 37 clh clh PROPN admet-144 42 38 , , PUNCT admet-144 42 39 obs obs PROPN admet-144 42 40 fnren fnren PROPN admet-144 42 41 fnmet fnmet PROPN admet-144 42 42 ml/(minΒ·kg ml/(minΒ·kg PROPN admet-144 42 43 ) ) PUNCT admet-144 42 44 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 42 45 ) ) PUNCT admet-144 42 46 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 42 47 ) ) PUNCT admet-144 42 48 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 42 49 ) ) PUNCT admet-144 42 50 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 42 51 ) ) PUNCT admet-144 42 52 ml/(minΒ·kg ml/(minΒ·kg PROPN admet-144 42 53 ) ) PUNCT admet-144 42 54 lovastatin lovastatin PROPN admet-144 42 55 acid acid PROPN admet-144 42 56 3/1 3/1 NUM admet-144 42 57 165.1 165.1 NUM admet-144 42 58 145.5 145.5 NUM admet-144 42 59 459.0 459.0 NUM admet-144 42 60 119.6 119.6 NUM admet-144 42 61 0.0 0.0 NUM admet-144 42 62 0.08 0.08 NUM admet-144 42 63 11.4 11.4 NUM admet-144 42 64 0.10 0.10 NUM admet-144 42 65 0.90 0.90 NUM admet-144 42 66 simvastatin simvastatin NOUN admet-144 42 67 acid acid NOUN admet-144 42 68 3/1 3/1 NUM admet-144 42 69 116.1 116.1 NUM admet-144 42 70 297.9 297.9 NUM admet-144 42 71 769.2 769.2 NUM admet-144 42 72 nd nd NUM admet-144 42 73 1.7 1.7 NUM admet-144 43 1 0.11 0.11 NUM admet-144 43 2 25.2 25.2 NUM admet-144 43 3 0.13 0.13 NUM admet-144 43 4 0.87 0.87 NUM admet-144 43 5 propanolol propanolol NOUN admet-144 43 6 4/2 4/2 NUM admet-144 43 7 300.7 300.7 NUM admet-144 43 8 276.3 276.3 NUM admet-144 43 9 110.8 110.8 NUM admet-144 43 10 29.2 29.2 NUM admet-144 43 11 6.8 6.8 NUM admet-144 43 12 0.11 0.11 NUM admet-144 43 13 12.8 12.8 NUM admet-144 43 14 0.01 0.01 NUM admet-144 43 15 0.99 0.99 NUM admet-144 43 16 quinidine quinidine NOUN admet-144 43 17 4/2 4/2 NUM admet-144 43 18 229.4 229.4 NUM admet-144 43 19 109.3 109.3 NUM admet-144 43 20 28.4 28.4 NUM admet-144 43 21 18.0 18.0 NUM admet-144 43 22 5.1 5.1 NUM admet-144 43 23 0.27 0.27 NUM admet-144 43 24 8.7 8.7 NUM admet-144 43 25 0.19 0.19 NUM admet-144 43 26 0.81 0.81 NUM admet-144 43 27 verapamil verapamil NOUN admet-144 43 28 2/2 2/2 NUM admet-144 43 29 0.0 0.0 NUM admet-144 43 30 258.2 258.2 NUM admet-144 43 31 127.7 127.7 NUM admet-144 43 32 33.4 33.4 NUM admet-144 43 33 8.1 8.1 NUM admet-144 43 34 0.13 0.13 NUM admet-144 43 35 13.7 13.7 NUM admet-144 43 36 0.03 0.03 NUM admet-144 43 37 0.97 0.97 NUM admet-144 43 38 ketoconazole ketoconazole NOUN admet-144 43 39 2/2 2/2 NUM admet-144 43 40 0.0 0.0 NUM admet-144 43 41 1568.5 1568.5 NUM admet-144 43 42 97.4 97.4 NUM admet-144 43 43 nd nd NUM admet-144 43 44 29.6 29.6 NUM admet-144 43 45 0.02 0.02 NUM admet-144 43 46 3.9 3.9 NUM admet-144 43 47 0.03 0.03 NUM admet-144 43 48 0.97 0.97 NUM admet-144 43 49 cerivastatin cerivastatin NOUN admet-144 43 50 4/2 4/2 NUM admet-144 43 51 221.5 221.5 NUM admet-144 43 52 243.8 243.8 NUM admet-144 43 53 46.9 46.9 NUM admet-144 43 54 nd nd NUM admet-144 43 55 0.0 0.0 NUM admet-144 43 56 0.02 0.02 NUM admet-144 43 57 3.4 3.4 NUM admet-144 43 58 0.00 0.00 NUM admet-144 43 59 1.00 1.00 NUM admet-144 43 60 fluvastatin fluvastatin NOUN admet-144 43 61 4/2 4/2 NUM admet-144 43 62 218.7 218.7 NUM admet-144 43 63 325.5 325.5 NUM admet-144 43 64 146.8 146.8 NUM admet-144 43 65 nd nd NUM admet-144 43 66 0.0 0.0 NUM admet-144 43 67 0.04 0.04 NUM admet-144 43 68 7.0 7.0 NUM admet-144 43 69 0.00 0.00 NUM admet-144 43 70 1.00 1.00 NUM admet-144 43 71 pitavastatin pitavastatin NOUN admet-144 43 72 4/2 4/2 NUM admet-144 43 73 364.3 364.3 NUM admet-144 43 74 258.7 258.7 NUM admet-144 43 75 17.7 17.7 NUM admet-144 43 76 nd nd NUM admet-144 43 77 0.0 0.0 NUM admet-144 43 78 0.07 0.07 NUM admet-144 43 79 3.5 3.5 NUM admet-144 43 80 0.00 0.00 NUM admet-144 43 81 nd nd NUM admet-144 43 82 aliskiren aliskiren PROPN admet-144 43 83 3/3 3/3 NUM admet-144 43 84 32.3 32.3 NUM admet-144 43 85 25.4 25.4 NUM admet-144 43 86 89.2 89.2 NUM admet-144 43 87 nd nd NUM admet-144 43 88 31.2 31.2 NUM admet-144 43 89 0.70 0.70 NUM admet-144 43 90 11.3 11.3 NUM admet-144 43 91 0.25 0.25 NUM admet-144 43 92 0.10 0.10 NUM admet-144 43 93 cimetidine cimetidine NOUN admet-144 43 94 3/3 3/3 NUM admet-144 43 95 3.0 3.0 NUM admet-144 43 96 3.6 3.6 NUM admet-144 43 97 528.7 528.7 NUM admet-144 43 98 3.2 3.2 NUM admet-144 43 99 0.2 0.2 NUM admet-144 43 100 0.84 0.84 NUM admet-144 43 101 2.7 2.7 NUM admet-144 43 102 0.84 0.84 NUM admet-144 43 103 0.14 0.14 NUM admet-144 43 104 digoxin digoxin NOUN admet-144 43 105 3/3 3/3 NUM admet-144 43 106 20.0 20.0 NUM admet-144 43 107 6.9 6.9 NUM admet-144 43 108 24.2 24.2 NUM admet-144 43 109 nd nd NUM admet-144 43 110 18.4 18.4 NUM admet-144 43 111 0.82 0.82 NUM admet-144 43 112 4.6 4.6 NUM admet-144 43 113 0.66 0.66 NUM admet-144 43 114 0.04 0.04 NUM admet-144 43 115 cyclospsorine cyclospsorine NOUN admet-144 43 116 a a DET admet-144 43 117 3/4 3/4 NUM admet-144 43 118 113.2 113.2 NUM admet-144 43 119 41.9 41.9 NUM admet-144 43 120 77.6 77.6 NUM admet-144 43 121 13.5 13.5 NUM admet-144 43 122 9.1 9.1 NUM admet-144 43 123 0.03 0.03 NUM admet-144 43 124 3.1 3.1 NUM admet-144 43 125 0.01 0.01 NUM admet-144 43 126 0.96 0.96 NUM admet-144 43 127 atorvastatin atorvastatin NOUN admet-144 43 128 4/4 4/4 NUM admet-144 43 129 140.4 140.4 NUM admet-144 43 130 57.7 57.7 NUM admet-144 43 131 64.6 64.6 NUM admet-144 43 132 254.4 254.4 NUM admet-144 43 133 11.8 11.8 NUM admet-144 43 134 0.08 0.08 NUM admet-144 43 135 5.9 5.9 NUM admet-144 43 136 0.02 0.02 NUM admet-144 43 137 0.69 0.69 NUM admet-144 43 138 furosemide furosemide ADJ admet-144 43 139 4/4 4/4 NUM admet-144 43 140 11.1 11.1 NUM admet-144 43 141 23.9 23.9 NUM admet-144 43 142 19.0 19.0 NUM admet-144 43 143 0.9 0.9 NUM admet-144 43 144 1.2 1.2 NUM admet-144 43 145 0.03 0.03 NUM admet-144 43 146 0.4 0.4 NUM admet-144 43 147 0.66 0.66 NUM admet-144 43 148 0.01 0.01 NUM admet-144 43 149 ciprofloxacin ciprofloxacin NOUN admet-144 43 150 4/4 4/4 NUM admet-144 43 151 7.0 7.0 NUM admet-144 43 152 22.9 22.9 NUM admet-144 43 153 22.0 22.0 NUM admet-144 43 154 nd nd NUM admet-144 43 155 0.0 0.0 NUM admet-144 43 156 0.69 0.69 NUM admet-144 43 157 4.5 4.5 NUM admet-144 43 158 0.60 0.60 NUM admet-144 43 159 0.12 0.12 NUM admet-144 43 160 valsartan valsartan PROPN admet-144 43 161 4/4 4/4 NUM admet-144 43 162 16.0 16.0 NUM admet-144 43 163 18.5 18.5 NUM admet-144 43 164 4.1 4.1 NUM admet-144 43 165 nd nd NUM admet-144 43 166 21.5 21.5 NUM admet-144 43 167 0.09 0.09 NUM admet-144 43 168 0.6 0.6 NUM admet-144 43 169 0.29 0.29 NUM admet-144 43 170 0.11 0.11 NUM admet-144 43 171 pravastatin pravastatin NOUN admet-144 43 172 4/4 4/4 NUM admet-144 43 173 57.9 57.9 NUM admet-144 43 174 36.0 36.0 NUM admet-144 43 175 0.9 0.9 NUM admet-144 43 176 5.3 5.3 NUM admet-144 43 177 2.2 2.2 NUM admet-144 43 178 0.97 0.97 NUM admet-144 43 179 10.4 10.4 NUM admet-144 43 180 0.47 0.47 NUM admet-144 43 181 0.30 0.30 NUM admet-144 43 182 rosuvastatin rosuvastatin NOUN admet-144 43 183 4/4 4/4 NUM admet-144 43 184 27.2 27.2 NUM admet-144 43 185 24.8 24.8 NUM admet-144 43 186 1.5 1.5 NUM admet-144 43 187 nd nd NUM admet-144 43 188 5.7 5.7 NUM admet-144 43 189 0.17 0.17 NUM admet-144 43 190 nd nd NUM admet-144 43 191 0.30 0.30 NUM admet-144 43 192 0.10 0.10 NUM admet-144 43 193 nd nd NOUN admet-144 43 194 : : PUNCT admet-144 43 195 not not PART admet-144 43 196 determined determined ADJ admet-144 43 197 or or CCONJ admet-144 43 198 experimental experimental ADJ admet-144 43 199 data datum NOUN admet-144 43 200 subject subject ADJ admet-144 43 201 to to ADP admet-144 43 202 a a DET admet-144 43 203 high high ADJ admet-144 43 204 degree degree NOUN admet-144 43 205 of of ADP admet-144 43 206 uncertainty uncertainty NOUN admet-144 43 207 as as SCONJ admet-144 43 208 discussed discuss VERB admet-144 43 209 elsewhere elsewhere ADV admet-144 43 210 [ [ X admet-144 43 211 4 4 NUM admet-144 43 212 ] ] PUNCT admet-144 43 213 . . PUNCT admet-144 44 1 with with ADP admet-144 44 2 exception exception NOUN admet-144 44 3 of of ADP admet-144 44 4 the the DET admet-144 44 5 hepatocyte hepatocyte NOUN admet-144 44 6 turn turn NOUN admet-144 44 7 - - PUNCT admet-144 44 8 over over ADP admet-144 44 9 data datum NOUN admet-144 44 10 [ [ X admet-144 44 11 5,6 5,6 NUM admet-144 44 12 ] ] X admet-144 44 13 all all PRON admet-144 44 14 hepatic hepatic VERB admet-144 44 15 in in ADP admet-144 44 16 vitro vitro X admet-144 44 17 and and CCONJ admet-144 44 18 in in ADP admet-144 44 19 vivo vivo ADJ admet-144 44 20 data datum NOUN admet-144 44 21 were be AUX admet-144 44 22 taken take VERB admet-144 44 23 from from ADP admet-144 44 24 previous previous ADJ admet-144 44 25 in in ADP admet-144 44 26 - - PUNCT admet-144 44 27 house house NOUN admet-144 44 28 manuscripts manuscript NOUN admet-144 44 29 [ [ X admet-144 44 30 1,4,7 1,4,7 NUM admet-144 44 31 ] ] PUNCT admet-144 44 32 . . PUNCT admet-144 45 1 ecm ecm PROPN admet-144 45 2 and and CCONJ admet-144 45 3 ecc ecc PROPN admet-144 45 4 class class NOUN admet-144 45 5 assignment assignment NOUN admet-144 45 6 was be AUX admet-144 45 7 performed perform VERB admet-144 45 8 according accord VERB admet-144 45 9 to to ADP admet-144 45 10 fig fig NOUN admet-144 45 11 . . PUNCT admet-144 46 1 1 1 NUM admet-144 46 2 and and CCONJ admet-144 46 3 fig fig NOUN admet-144 46 4 . . PUNCT admet-144 47 1 6 6 NUM admet-144 47 2 , , PUNCT admet-144 47 3 respectively respectively ADV admet-144 47 4 ( ( PUNCT admet-144 47 5 underlying underlying ADJ admet-144 47 6 working work VERB admet-144 47 7 principle principle NOUN admet-144 47 8 : : PUNCT admet-144 47 9 class class NOUN admet-144 47 10 1 1 NUM admet-144 47 11 or or CCONJ admet-144 47 12 3 3 NUM admet-144 47 13 if if SCONJ admet-144 47 14 2Β·pseff 2Β·pseff PROPN admet-144 47 15 < < X admet-144 47 16 ( ( PUNCT admet-144 47 17 clint clint NOUN admet-144 47 18 , , PUNCT admet-144 47 19 met meet VERB admet-144 47 20 , , PUNCT admet-144 47 21 hlm hlm X admet-144 47 22 + + CCONJ admet-144 47 23 clint clint NOUN admet-144 47 24 , , PUNCT admet-144 47 25 sec sec PROPN admet-144 47 26 ) ) PUNCT admet-144 47 27 , , PUNCT admet-144 47 28 otherwise otherwise ADV admet-144 47 29 class class NOUN admet-144 47 30 2 2 NUM admet-144 47 31 or or CCONJ admet-144 47 32 4 4 NUM admet-144 47 33 ) ) PUNCT admet-144 47 34 . . PUNCT admet-144 48 1 metabolic metabolic NOUN admet-144 48 2 clearance clearance NOUN admet-144 48 3 data datum NOUN admet-144 48 4 from from ADP admet-144 48 5 human human ADJ admet-144 48 6 liver liver NOUN admet-144 48 7 microsomes microsome NOUN admet-144 48 8 and and CCONJ admet-144 48 9 human human ADJ admet-144 48 10 hepatocytes hepatocyte NOUN admet-144 48 11 are be AUX admet-144 48 12 labeled label VERB admet-144 48 13 with with ADP admet-144 48 14 the the DET admet-144 48 15 subscripts subscript NOUN admet-144 48 16 hlm hlm ADJ admet-144 48 17 and and CCONJ admet-144 48 18 hh hh ADJ admet-144 48 19 , , PUNCT admet-144 48 20 respectively respectively ADV admet-144 48 21 . . PUNCT admet-144 49 1 fnmet fnmet PROPN admet-144 49 2 (= (= X admet-144 49 3 clmet clmet PROPN admet-144 49 4 , , PUNCT admet-144 49 5 obs obs PROPN admet-144 49 6 / / SYM admet-144 49 7 cltot cltot PROPN admet-144 49 8 , , PUNCT admet-144 49 9 obs obs PROPN admet-144 49 10 ) ) PUNCT admet-144 49 11 and and CCONJ admet-144 49 12 fnren fnren PROPN admet-144 49 13 (= (= NOUN admet-144 49 14 clren clren PROPN admet-144 49 15 , , PUNCT admet-144 49 16 obs obs PROPN admet-144 49 17 / / SYM admet-144 49 18 cltot cltot PROPN admet-144 49 19 , , PUNCT admet-144 49 20 obs obs PROPN admet-144 49 21 ) ) PUNCT admet-144 49 22 values value NOUN admet-144 49 23 were be AUX admet-144 49 24 calculated calculate VERB admet-144 49 25 from from ADP admet-144 49 26 the the DET admet-144 49 27 observed observed ADJ admet-144 49 28 total total NOUN admet-144 49 29 ( ( PUNCT admet-144 49 30 cltot cltot PROPN admet-144 49 31 , , PUNCT admet-144 49 32 obs obs PROPN admet-144 49 33 ) ) PUNCT admet-144 49 34 , , PUNCT admet-144 49 35 renal renal ADJ admet-144 49 36 ( ( PUNCT admet-144 49 37 clren clren PROPN admet-144 49 38 , , PUNCT admet-144 49 39 obs obs PROPN admet-144 49 40 ) ) PUNCT admet-144 49 41 and and CCONJ admet-144 49 42 metabolic metabolic NOUN admet-144 49 43 ( ( PUNCT admet-144 49 44 clmet clmet NOUN admet-144 49 45 , , PUNCT admet-144 49 46 obs obs PROPN admet-144 49 47 ) ) PUNCT admet-144 49 48 clearances clearance NOUN admet-144 49 49 as as SCONJ admet-144 49 50 derived derive VERB admet-144 49 51 from from ADP admet-144 49 52 peroral peroral ADJ admet-144 49 53 human human PROPN admet-144 49 54 mass mass PROPN admet-144 49 55 balance balance NOUN admet-144 49 56 studies study NOUN admet-144 49 57 taking take VERB admet-144 49 58 into into ADP admet-144 49 59 consideration consideration NOUN admet-144 49 60 the the DET admet-144 49 61 estimated estimate VERB admet-144 49 62 absolute absolute ADJ admet-144 49 63 oral oral ADJ admet-144 49 64 bioavailability bioavailability NOUN admet-144 49 65 ( ( PUNCT admet-144 49 66 f f NOUN admet-144 49 67 ) ) PUNCT admet-144 49 68 . . PUNCT admet-144 50 1 thereof thereof ADV admet-144 50 2 , , PUNCT admet-144 50 3 fnh fnh X admet-144 50 4 (= (= X admet-144 50 5 1fnren 1fnren NUM admet-144 50 6 ) ) PUNCT admet-144 50 7 and and CCONJ admet-144 50 8 fnsec fnsec PROPN admet-144 50 9 (= (= PUNCT admet-144 50 10 fnhfnmet fnhfnmet PROPN admet-144 50 11 ) ) PUNCT admet-144 50 12 values value NOUN admet-144 50 13 discussed discuss VERB admet-144 50 14 in in ADP admet-144 50 15 this this DET admet-144 50 16 manuscript manuscript NOUN admet-144 50 17 can can AUX admet-144 50 18 be be AUX admet-144 50 19 calculated calculate VERB admet-144 50 20 . . PUNCT admet-144 51 1 camenisch camenisch PROPN admet-144 51 2 et et PROPN admet-144 51 3 al al PROPN admet-144 51 4 . . PROPN admet-144 51 5 admet admet PROPN admet-144 51 6 & & CCONJ admet-144 51 7 dmpk dmpk PROPN admet-144 51 8 3(1 3(1 NUM admet-144 51 9 ) ) PUNCT admet-144 51 10 ( ( PUNCT admet-144 51 11 2015 2015 NUM admet-144 51 12 ) ) PUNCT admet-144 51 13 1 1 NUM admet-144 51 14 - - SYM admet-144 51 15 14 14 NUM admet-144 51 16 4 4 NUM admet-144 51 17 role role NOUN admet-144 51 18 of of ADP admet-144 51 19 membrane membrane NOUN admet-144 51 20 permeability permeability NOUN admet-144 51 21 in in ADP admet-144 51 22 hepatic hepatic ADJ admet-144 51 23 elimination elimination NOUN admet-144 51 24 the the DET admet-144 51 25 likelihood likelihood NOUN admet-144 51 26 that that SCONJ admet-144 51 27 drugs drug NOUN admet-144 51 28 will will AUX admet-144 51 29 be be AUX admet-144 51 30 subject subject ADJ admet-144 51 31 to to ADP admet-144 51 32 enzyme enzyme NOUN admet-144 51 33 and/or and/or CCONJ admet-144 51 34 canalicular canalicular ADJ admet-144 51 35 efflux efflux NOUN admet-144 51 36 transporter transporter NOUN admet-144 51 37 activities activity NOUN admet-144 51 38 in in ADP admet-144 51 39 the the DET admet-144 51 40 liver liver NOUN admet-144 51 41 depends depend VERB admet-144 51 42 on on ADP admet-144 51 43 the the DET admet-144 51 44 extent extent NOUN admet-144 51 45 of of ADP admet-144 51 46 their their PRON admet-144 51 47 sinusoidal sinusoidal ADJ admet-144 51 48 membrane membrane NOUN admet-144 51 49 permeation permeation NOUN admet-144 51 50 . . PUNCT admet-144 52 1 for for ADP admet-144 52 2 the the DET admet-144 52 3 compounds compound NOUN admet-144 52 4 in in ADP admet-144 52 5 our our PRON admet-144 52 6 dataset dataset NOUN admet-144 52 7 ( ( PUNCT admet-144 52 8 table table NOUN admet-144 52 9 1 1 NUM admet-144 52 10 ) ) PUNCT admet-144 52 11 this this PRON admet-144 52 12 is be AUX admet-144 52 13 illustrated illustrate VERB admet-144 52 14 in in ADP admet-144 52 15 fig fig NOUN admet-144 52 16 . . PUNCT admet-144 53 1 2 2 NUM admet-144 53 2 depicting depict VERB admet-144 53 3 the the DET admet-144 53 4 relationship relationship NOUN admet-144 53 5 between between ADP admet-144 53 6 ( ( PUNCT admet-144 53 7 in in ADP admet-144 53 8 vitro vitro X admet-144 53 9 ) ) PUNCT admet-144 53 10 sinusoidal sinusoidal ADJ admet-144 53 11 passive passive ADJ admet-144 53 12 uptake uptake NOUN admet-144 53 13 ( ( PUNCT admet-144 53 14 psinf psinf ADJ admet-144 53 15 , , PUNCT admet-144 53 16 pas pas NOUN admet-144 53 17 ) ) PUNCT admet-144 53 18 and and CCONJ admet-144 53 19 the the DET admet-144 53 20 fractional fractional ADJ admet-144 53 21 contribution contribution NOUN admet-144 53 22 of of ADP admet-144 53 23 metabolism metabolism NOUN admet-144 53 24 ( ( PUNCT admet-144 53 25 fnmet fnmet ADJ admet-144 53 26 , , PUNCT admet-144 53 27 panel panel NOUN admet-144 53 28 a a NOUN admet-144 53 29 ) ) PUNCT admet-144 53 30 or or CCONJ admet-144 53 31 biliary biliary NOUN admet-144 53 32 secretion secretion NOUN admet-144 53 33 ( ( PUNCT admet-144 53 34 fnsec fnsec PROPN admet-144 53 35 , , PUNCT admet-144 53 36 panel panel NOUN admet-144 53 37 b b NOUN admet-144 53 38 ) ) PUNCT admet-144 53 39 to to PART admet-144 53 40 overall overall VERB admet-144 53 41 in in ADP admet-144 53 42 vivo vivo ADJ admet-144 53 43 elimination elimination NOUN admet-144 53 44 . . PUNCT admet-144 54 1 figure figure NOUN admet-144 54 2 2 2 NUM admet-144 54 3 . . PUNCT admet-144 55 1 correlation correlation NOUN admet-144 55 2 of of ADP admet-144 55 3 sinusoidal sinusoidal ADJ admet-144 55 4 hepatic hepatic ADJ admet-144 55 5 uptake uptake ADJ admet-144 55 6 clearances clearance NOUN admet-144 55 7 ( ( PUNCT admet-144 55 8 psinf psinf ADJ admet-144 55 9 , , PUNCT admet-144 55 10 pas pas NOUN admet-144 55 11 or or CCONJ admet-144 55 12 psinf psinf VERB admet-144 55 13 ) ) PUNCT admet-144 55 14 with with ADP admet-144 55 15 the the DET admet-144 55 16 fractional fractional ADJ admet-144 55 17 contributions contribution NOUN admet-144 55 18 of of ADP admet-144 55 19 metabolic metabolic NOUN admet-144 55 20 ( ( PUNCT admet-144 55 21 panel panel NOUN admet-144 55 22 a a X admet-144 55 23 ) ) PUNCT admet-144 55 24 , , PUNCT admet-144 55 25 biliary biliary NOUN admet-144 55 26 ( ( PUNCT admet-144 55 27 panel panel NOUN admet-144 55 28 b b NOUN admet-144 55 29 ) ) PUNCT admet-144 55 30 , , PUNCT admet-144 55 31 hepatic hepatic NOUN admet-144 55 32 ( ( PUNCT admet-144 55 33 panel panel NOUN admet-144 55 34 c c NOUN admet-144 55 35 ) ) PUNCT admet-144 55 36 and and CCONJ admet-144 55 37 renal renal ADJ admet-144 55 38 ( ( PUNCT admet-144 55 39 panel panel NOUN admet-144 55 40 d d NOUN admet-144 55 41 ) ) PUNCT admet-144 55 42 clearance clearance NOUN admet-144 55 43 to to PART admet-144 55 44 overall overall NOUN admet-144 55 45 in in ADP admet-144 55 46 vivo vivo ADJ admet-144 55 47 elimination elimination NOUN admet-144 55 48 . . PUNCT admet-144 56 1 an an DET admet-144 56 2 increase increase NOUN admet-144 56 3 in in ADP admet-144 56 4 lipophilicity lipophilicity NOUN admet-144 56 5 is be AUX admet-144 56 6 well well ADV admet-144 56 7 known known ADJ admet-144 56 8 to to PART admet-144 56 9 promote promote VERB admet-144 56 10 the the DET admet-144 56 11 passive passive ADJ admet-144 56 12 permeability permeability NOUN admet-144 56 13 potential potential NOUN admet-144 56 14 of of ADP admet-144 56 15 drugs drug NOUN admet-144 56 16 as as ADV admet-144 56 17 well well ADV admet-144 56 18 as as ADP admet-144 56 19 their their PRON admet-144 56 20 affinity affinity NOUN admet-144 56 21 to to ADP admet-144 56 22 drug drug NOUN admet-144 56 23 metabolizing metabolize VERB admet-144 56 24 enzymes enzyme NOUN admet-144 56 25 [ [ X admet-144 56 26 8 8 NUM admet-144 56 27 ] ] PUNCT admet-144 56 28 . . PUNCT admet-144 57 1 above above ADP admet-144 57 2 observed observe VERB admet-144 57 3 inter inter NOUN admet-144 57 4 - - NOUN admet-144 57 5 relationship relationship NOUN admet-144 57 6 , , PUNCT admet-144 57 7 as as SCONJ admet-144 57 8 depicted depict VERB admet-144 57 9 in in ADP admet-144 57 10 fig fig NOUN admet-144 57 11 . . PUNCT admet-144 58 1 2 2 NUM admet-144 58 2 ( ( PUNCT admet-144 58 3 panel panel NOUN admet-144 58 4 a a PRON admet-144 58 5 ) ) PUNCT admet-144 58 6 , , PUNCT admet-144 58 7 is be AUX admet-144 58 8 therefore therefore ADV admet-144 58 9 not not PART admet-144 58 10 very very ADV admet-144 58 11 surprising surprising ADJ admet-144 58 12 . . PUNCT admet-144 59 1 the the DET admet-144 59 2 association association NOUN admet-144 59 3 of of ADP admet-144 59 4 permeability permeability NOUN admet-144 59 5 and and CCONJ admet-144 59 6 enzyme enzyme NOUN admet-144 59 7 activity activity NOUN admet-144 59 8 allows allow VERB admet-144 59 9 to to PART admet-144 59 10 define define VERB admet-144 59 11 an an DET admet-144 59 12 approximate approximate ADJ admet-144 59 13 sinusoidal sinusoidal NOUN admet-144 59 14 permeability permeability NOUN admet-144 59 15 threshold threshold NOUN admet-144 59 16 above above ADP admet-144 59 17 which which PRON admet-144 59 18 drug drug NOUN admet-144 59 19 elimination elimination NOUN admet-144 59 20 seems seems AUX admet-144 59 21 predominantly predominantly ADV admet-144 59 22 driven drive VERB admet-144 59 23 by by ADP admet-144 59 24 metabolism metabolism NOUN admet-144 59 25 ( ( PUNCT admet-144 59 26 > > X admet-144 59 27 200 200 NUM admet-144 59 28 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 59 29 ) ) PUNCT admet-144 59 30 ) ) PUNCT admet-144 59 31 . . PUNCT admet-144 60 1 the the DET admet-144 60 2 corresponding corresponding ADJ admet-144 60 3 plot plot NOUN admet-144 60 4 of of ADP admet-144 60 5 psinf psinf NOUN admet-144 60 6 , , PUNCT admet-144 60 7 pas pas PROPN admet-144 60 8 vs vs ADP admet-144 60 9 fnsec fnsec PROPN admet-144 60 10 reveals reveal VERB admet-144 60 11 that that SCONJ admet-144 60 12 compound compound NOUN admet-144 60 13 recognition recognition NOUN admet-144 60 14 by by ADP admet-144 60 15 canalicular canalicular ADJ admet-144 60 16 efflux efflux NOUN admet-144 60 17 transporters transporter NOUN admet-144 60 18 , , PUNCT admet-144 60 19 in in ADP admet-144 60 20 contrast contrast NOUN admet-144 60 21 to to ADP admet-144 60 22 fnmet fnmet NOUN admet-144 60 23 , , PUNCT admet-144 60 24 is be AUX admet-144 60 25 by by ADP admet-144 60 26 some some DET admet-144 60 27 means mean NOUN admet-144 60 28 inversely inversely ADV admet-144 60 29 correlated correlate VERB admet-144 60 30 with with ADP admet-144 60 31 rising rise VERB admet-144 60 32 sinusoidal sinusoidal ADJ admet-144 60 33 permeability permeability NOUN admet-144 60 34 ( ( PUNCT admet-144 60 35 fig fig NOUN admet-144 60 36 . . PUNCT admet-144 61 1 2 2 NUM admet-144 61 2 , , PUNCT admet-144 61 3 panel panel NOUN admet-144 61 4 b b NOUN admet-144 61 5 ) ) PUNCT admet-144 61 6 . . PUNCT admet-144 62 1 fig fig NOUN admet-144 62 2 . . PUNCT admet-144 63 1 3 3 NUM admet-144 63 2 shows show VERB admet-144 63 3 the the DET admet-144 63 4 contribution contribution NOUN admet-144 63 5 of of ADP admet-144 63 6 the the DET admet-144 63 7 measured measure VERB admet-144 63 8 in in ADP admet-144 63 9 vivo vivo ADJ admet-144 63 10 metabolic metabolic NOUN admet-144 63 11 clearance clearance NOUN admet-144 63 12 to to ADP admet-144 63 13 the the DET admet-144 63 14 in in ADP admet-144 63 15 vivo vivo ADJ admet-144 63 16 hepatic hepatic ADJ admet-144 63 17 clearance clearance NOUN admet-144 63 18 (= (= ADP admet-144 63 19 fnmet fnmet X admet-144 63 20 / / SYM admet-144 63 21 fnh fnh PROPN admet-144 63 22 ) ) PUNCT admet-144 63 23 for for ADP admet-144 63 24 the the DET admet-144 63 25 compounds compound NOUN admet-144 63 26 in in ADP admet-144 63 27 our our PRON admet-144 63 28 dataset dataset NOUN admet-144 63 29 . . PUNCT admet-144 64 1 not not PART admet-144 64 2 astonishingly astonishingly ADV admet-144 64 3 , , PUNCT admet-144 64 4 the the DET admet-144 64 5 compounds compound NOUN admet-144 64 6 with with ADP admet-144 64 7 a a DET admet-144 64 8 high high ADJ admet-144 64 9 ( ( PUNCT admet-144 64 10 total total ADJ admet-144 64 11 ) ) PUNCT admet-144 64 12 sinusoidal sinusoidal ADJ admet-144 64 13 permeability permeability NOUN admet-144 64 14 are be AUX admet-144 64 15 predominantly predominantly ADV admet-144 64 16 cleared clear VERB admet-144 64 17 via via ADP admet-144 64 18 hepatic hepatic ADJ admet-144 64 19 metabolism metabolism NOUN admet-144 64 20 , , PUNCT admet-144 64 21 while while SCONJ admet-144 64 22 the the DET admet-144 64 23 contribution contribution NOUN admet-144 64 24 of of ADP admet-144 64 25 metabolism metabolism NOUN admet-144 64 26 generally generally ADV admet-144 64 27 decreases decrease VERB admet-144 64 28 for for ADP admet-144 64 29 lower low ADJ admet-144 64 30 permeability permeability NOUN admet-144 64 31 compounds compound NOUN admet-144 64 32 apparently apparently ADV admet-144 64 33 accompanied accompany VERB admet-144 64 34 by by ADP admet-144 64 35 an an DET admet-144 64 36 increasing increase VERB admet-144 64 37 contribution contribution NOUN admet-144 64 38 of of ADP admet-144 64 39 active active ADJ admet-144 64 40 canalicular canalicular ADJ admet-144 64 41 secretion secretion NOUN admet-144 64 42 . . PUNCT admet-144 65 1 admet admet PROPN admet-144 65 2 & & CCONJ admet-144 65 3 dmpk dmpk PROPN admet-144 65 4 3(1 3(1 NUM admet-144 65 5 ) ) PUNCT admet-144 65 6 ( ( PUNCT admet-144 65 7 2015 2015 NUM admet-144 65 8 ) ) PUNCT admet-144 65 9 1 1 NUM admet-144 65 10 - - SYM admet-144 65 11 14 14 NUM admet-144 65 12 extended extended ADJ admet-144 65 13 clearance clearance NOUN admet-144 65 14 concept concept NOUN admet-144 65 15 classification classification NOUN admet-144 65 16 system system NOUN admet-144 65 17 ( ( PUNCT admet-144 65 18 ecccs ecccs NOUN admet-144 65 19 ) ) PUNCT admet-144 65 20 doi doi NOUN admet-144 65 21 : : PUNCT admet-144 65 22 10.5599 10.5599 NUM admet-144 65 23 / / SYM admet-144 65 24 admet.3.1.144 admet.3.1.144 PROPN admet-144 65 25 5 5 NUM admet-144 65 26 figure figure NOUN admet-144 65 27 3 3 NUM admet-144 65 28 . . NOUN admet-144 65 29 contribution contribution NOUN admet-144 65 30 of of ADP admet-144 65 31 in in ADP admet-144 65 32 vivo vivo ADJ admet-144 65 33 metabolism metabolism NOUN admet-144 65 34 to to ADP admet-144 65 35 overall overall ADJ admet-144 65 36 hepatic hepatic ADJ admet-144 65 37 clearance clearance NOUN admet-144 65 38 for for ADP admet-144 65 39 the the DET admet-144 65 40 dataset dataset NOUN admet-144 65 41 in in ADP admet-144 65 42 table table NOUN admet-144 65 43 1 1 NUM admet-144 65 44 . . PUNCT admet-144 66 1 the the DET admet-144 66 2 dotted dotted ADJ admet-144 66 3 line line NOUN admet-144 66 4 separates separate VERB admet-144 66 5 the the DET admet-144 66 6 high high ADJ admet-144 66 7 permeability permeability NOUN admet-144 66 8 compounds compound NOUN admet-144 66 9 ( ( PUNCT admet-144 66 10 green green ADJ admet-144 66 11 bars bar NOUN admet-144 66 12 ) ) PUNCT admet-144 66 13 from from ADP admet-144 66 14 the the DET admet-144 66 15 low low ADJ admet-144 66 16 permeability permeability NOUN admet-144 66 17 drugs drug NOUN admet-144 66 18 ( ( PUNCT admet-144 66 19 orange orange NOUN admet-144 66 20 bars bar NOUN admet-144 66 21 ) ) PUNCT admet-144 66 22 as as SCONJ admet-144 66 23 determined determine VERB admet-144 66 24 by by ADP admet-144 66 25 uptake uptake ADJ admet-144 66 26 experiments experiment NOUN admet-144 66 27 in in ADP admet-144 66 28 suspended suspend VERB admet-144 66 29 hepatocytes hepatocyte NOUN admet-144 66 30 ( ( PUNCT admet-144 66 31 psinf psinf ADJ admet-144 66 32 threshold threshold NOUN admet-144 66 33 : : PUNCT admet-144 66 34 200 200 NUM admet-144 66 35 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 66 36 ) ) PUNCT admet-144 66 37 ) ) PUNCT admet-144 66 38 . . PUNCT admet-144 67 1 hepatic hepatic PROPN admet-144 67 2 versus versus ADP admet-144 67 3 non non ADJ admet-144 67 4 - - ADJ admet-144 67 5 hepatic hepatic ADJ admet-144 67 6 elimination elimination NOUN admet-144 67 7 figure figure NOUN admet-144 67 8 2 2 NUM admet-144 67 9 ( ( PUNCT admet-144 67 10 panel panel NOUN admet-144 67 11 c c NOUN admet-144 67 12 ) ) PUNCT admet-144 67 13 illustrates illustrate VERB admet-144 67 14 the the DET admet-144 67 15 relationship relationship NOUN admet-144 67 16 between between ADP admet-144 67 17 passive passive ADJ admet-144 67 18 sinusoidal sinusoidal NOUN admet-144 67 19 uptake uptake NOUN admet-144 67 20 ( ( PUNCT admet-144 67 21 psinf psinf ADJ admet-144 67 22 , , PUNCT admet-144 67 23 pas pas NOUN admet-144 67 24 ) ) PUNCT admet-144 67 25 and and CCONJ admet-144 67 26 the the DET admet-144 67 27 observed observe VERB admet-144 67 28 ( ( PUNCT admet-144 67 29 in in ADP admet-144 67 30 vivo vivo NOUN admet-144 67 31 ) ) PUNCT admet-144 67 32 fractional fractional ADJ admet-144 67 33 contribution contribution NOUN admet-144 67 34 of of ADP admet-144 67 35 hepatic hepatic ADJ admet-144 67 36 clearance clearance NOUN admet-144 67 37 to to ADP admet-144 67 38 overall overall ADJ admet-144 67 39 drug drug NOUN admet-144 67 40 elimination elimination NOUN admet-144 67 41 fnh fnh PROPN admet-144 67 42 . . PUNCT admet-144 68 1 from from ADP admet-144 68 2 this this DET admet-144 68 3 illustration illustration NOUN admet-144 68 4 it it PRON admet-144 68 5 appears appear VERB admet-144 68 6 that that SCONJ admet-144 68 7 a a DET admet-144 68 8 sinusoidal sinusoidal ADJ admet-144 68 9 permeability permeability NOUN admet-144 68 10 of of ADP admet-144 68 11 above above ADP admet-144 68 12 40 40 NUM admet-144 68 13 - - SYM admet-144 68 14 60 60 NUM admet-144 68 15 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 68 16 ) ) PUNCT admet-144 68 17 will will AUX admet-144 68 18 result result VERB admet-144 68 19 in in ADP admet-144 68 20 predominant predominant ADJ admet-144 68 21 hepatic hepatic ADJ admet-144 68 22 clearance clearance NOUN admet-144 68 23 ( ( PUNCT admet-144 68 24 > > X admet-144 68 25 80 80 NUM admet-144 68 26 % % NOUN admet-144 68 27 ) ) PUNCT admet-144 68 28 . . PUNCT admet-144 69 1 numerous numerous ADJ admet-144 69 2 data datum NOUN admet-144 69 3 demonstrates demonstrate VERB admet-144 69 4 that that SCONJ admet-144 69 5 permeability permeability NOUN admet-144 69 6 also also ADV admet-144 69 7 exerts exert VERB admet-144 69 8 a a DET admet-144 69 9 key key ADJ admet-144 69 10 role role NOUN admet-144 69 11 in in ADP admet-144 69 12 renal renal ADJ admet-144 69 13 elimination elimination NOUN admet-144 69 14 similar similar ADJ admet-144 69 15 to to ADP admet-144 69 16 the the DET admet-144 69 17 one one NOUN admet-144 69 18 discussed discuss VERB admet-144 69 19 here here ADV admet-144 69 20 for for ADP admet-144 69 21 liver liver NOUN admet-144 69 22 [ [ X admet-144 69 23 4 4 NUM admet-144 69 24 ] ] PUNCT admet-144 69 25 . . PUNCT admet-144 70 1 it it PRON admet-144 70 2 could could AUX admet-144 70 3 be be AUX admet-144 70 4 demonstrated demonstrate VERB admet-144 70 5 that that SCONJ admet-144 70 6 for for ADP admet-144 70 7 the the DET admet-144 70 8 highly highly ADV admet-144 70 9 permeable permeable ADJ admet-144 70 10 compounds compound NOUN admet-144 70 11 , , PUNCT admet-144 70 12 despite despite SCONJ admet-144 70 13 significant significant ADJ admet-144 70 14 tubular tubular ADJ admet-144 70 15 secretion secretion NOUN admet-144 70 16 , , PUNCT admet-144 70 17 reabsorption reabsorption NOUN admet-144 70 18 from from ADP admet-144 70 19 the the DET admet-144 70 20 tubule tubule NOUN admet-144 70 21 back back ADV admet-144 70 22 into into ADP admet-144 70 23 the the DET admet-144 70 24 blood blood NOUN admet-144 70 25 is be AUX admet-144 70 26 so so ADV admet-144 70 27 extensive extensive ADJ admet-144 70 28 that that SCONJ admet-144 70 29 overall overall ADJ admet-144 70 30 renal renal ADJ admet-144 70 31 clearance clearance NOUN admet-144 70 32 for for ADP admet-144 70 33 these these DET admet-144 70 34 compounds compound NOUN admet-144 70 35 will will AUX admet-144 70 36 be be AUX admet-144 70 37 low low ADJ admet-144 70 38 . . PUNCT admet-144 71 1 for for ADP admet-144 71 2 the the DET admet-144 71 3 low low ADJ admet-144 71 4 permeable permeable ADJ admet-144 71 5 compounds compound NOUN admet-144 71 6 on on ADP admet-144 71 7 the the DET admet-144 71 8 other other ADJ admet-144 71 9 hand hand NOUN admet-144 71 10 reabsorption reabsorption NOUN admet-144 71 11 , , PUNCT admet-144 71 12 in in ADP admet-144 71 13 agreement agreement NOUN admet-144 71 14 with with ADP admet-144 71 15 their their PRON admet-144 71 16 reduced reduce VERB admet-144 71 17 permeability permeability NOUN admet-144 71 18 potential potential NOUN admet-144 71 19 , , PUNCT admet-144 71 20 will will AUX admet-144 71 21 be be AUX admet-144 71 22 much much ADV admet-144 71 23 less less ADJ admet-144 71 24 . . PUNCT admet-144 72 1 as as SCONJ admet-144 72 2 illustrated illustrate VERB admet-144 72 3 in in ADP admet-144 72 4 fig fig NOUN admet-144 72 5 . . PUNCT admet-144 73 1 4 4 NUM admet-144 73 2 , , PUNCT admet-144 73 3 for for ADP admet-144 73 4 all all DET admet-144 73 5 compounds compound NOUN admet-144 73 6 in in ADP admet-144 73 7 our our PRON admet-144 73 8 dataset dataset NOUN admet-144 73 9 with with ADP admet-144 73 10 a a DET admet-144 73 11 ( ( PUNCT admet-144 73 12 passive passive ADJ admet-144 73 13 ) ) PUNCT admet-144 73 14 sinusoidal sinusoidal ADJ admet-144 73 15 permeability permeability NOUN admet-144 73 16 beyond beyond ADP admet-144 73 17 40 40 NUM admet-144 73 18 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 73 19 ) ) PUNCT admet-144 73 20 renal renal ADJ admet-144 73 21 clearance clearance NOUN admet-144 73 22 is be AUX admet-144 73 23 a a DET admet-144 73 24 minor minor ADJ admet-144 73 25 route route NOUN admet-144 73 26 of of ADP admet-144 73 27 elimination elimination NOUN admet-144 73 28 ( ( PUNCT admet-144 73 29 fnren fnren VERB admet-144 73 30 < < X admet-144 73 31 20 20 NUM admet-144 73 32 % % NOUN admet-144 73 33 ) ) PUNCT admet-144 73 34 . . PUNCT admet-144 74 1 for for ADP admet-144 74 2 the the DET admet-144 74 3 lower low ADJ admet-144 74 4 permeable permeable ADJ admet-144 74 5 compounds compound VERB admet-144 74 6 the the DET admet-144 74 7 fractional fractional ADJ admet-144 74 8 contribution contribution NOUN admet-144 74 9 of of ADP admet-144 74 10 renal renal ADJ admet-144 74 11 clearance clearance NOUN admet-144 74 12 to to ADP admet-144 74 13 total total ADJ admet-144 74 14 body body NOUN admet-144 74 15 clearance clearance NOUN admet-144 74 16 exceeds exceed VERB admet-144 74 17 20 20 NUM admet-144 74 18 % % NOUN admet-144 74 19 or or CCONJ admet-144 74 20 even even ADV admet-144 74 21 represents represent VERB admet-144 74 22 the the DET admet-144 74 23 predominant predominant ADJ admet-144 74 24 route route NOUN admet-144 74 25 of of ADP admet-144 74 26 elimination elimination NOUN admet-144 74 27 suggesting suggest VERB admet-144 74 28 that that SCONJ admet-144 74 29 hepatic hepatic ADJ admet-144 74 30 and and CCONJ admet-144 74 31 renal renal ADJ admet-144 74 32 elimination elimination NOUN admet-144 74 33 are be AUX admet-144 74 34 somehow somehow ADV admet-144 74 35 complementary complementary ADJ admet-144 74 36 with with ADP admet-144 74 37 regards regard NOUN admet-144 74 38 to to ADP admet-144 74 39 the the DET admet-144 74 40 role role NOUN admet-144 74 41 of of ADP admet-144 74 42 sinusoidal sinusoidal ADJ admet-144 74 43 permeability permeability NOUN admet-144 74 44 in in ADP admet-144 74 45 drug drug NOUN admet-144 74 46 elimination elimination NOUN admet-144 74 47 . . PUNCT admet-144 75 1 figure figure NOUN admet-144 75 2 4 4 NUM admet-144 75 3 . . PUNCT admet-144 76 1 contributions contribution NOUN admet-144 76 2 of of ADP admet-144 76 3 the the DET admet-144 76 4 observed observe VERB admet-144 76 5 renal renal ADJ admet-144 76 6 ( ( PUNCT admet-144 76 7 red red ADJ admet-144 76 8 bars bar NOUN admet-144 76 9 ) ) PUNCT admet-144 76 10 and and CCONJ admet-144 76 11 hepatic hepatic ADJ admet-144 76 12 ( ( PUNCT admet-144 76 13 blue blue ADJ admet-144 76 14 bars bar NOUN admet-144 76 15 ) ) PUNCT admet-144 76 16 clearance clearance NOUN admet-144 76 17 pathways pathway NOUN admet-144 76 18 to to ADP admet-144 76 19 the the DET admet-144 76 20 total total ADJ admet-144 76 21 body body NOUN admet-144 76 22 clearance clearance NOUN admet-144 76 23 ( ( PUNCT admet-144 76 24 cltot cltot PROPN admet-144 76 25 , , PUNCT admet-144 76 26 obs obs PROPN admet-144 76 27 = = PUNCT admet-144 76 28 clh clh PROPN admet-144 76 29 , , PUNCT admet-144 76 30 obs obs PROPN admet-144 76 31 + + CCONJ admet-144 76 32 clren clren PROPN admet-144 76 33 , , PUNCT admet-144 76 34 obs obs PROPN admet-144 76 35 ) ) PUNCT admet-144 76 36 for for ADP admet-144 76 37 the the DET admet-144 76 38 compounds compound NOUN admet-144 76 39 in in ADP admet-144 76 40 table table NOUN admet-144 76 41 1 1 NUM admet-144 76 42 . . PUNCT admet-144 77 1 the the DET admet-144 77 2 dotted dotted ADJ admet-144 77 3 line line NOUN admet-144 77 4 separates separate VERB admet-144 77 5 the the DET admet-144 77 6 compounds compound NOUN admet-144 77 7 with with ADP admet-144 77 8 a a DET admet-144 77 9 psinf psinf ADJ admet-144 77 10 , , PUNCT admet-144 77 11 pas pas NOUN admet-144 77 12 value value NOUN admet-144 77 13 greater great ADJ admet-144 77 14 ( ( PUNCT admet-144 77 15 left leave VERB admet-144 77 16 part part NOUN admet-144 77 17 ) ) PUNCT admet-144 77 18 or or CCONJ admet-144 77 19 lower low ADJ admet-144 77 20 ( ( PUNCT admet-144 77 21 right right ADJ admet-144 77 22 part part NOUN admet-144 77 23 ) ) PUNCT admet-144 77 24 than than ADP admet-144 77 25 40 40 NUM admet-144 77 26 ml/(minΒ·kg ml/(minΒ·kg NOUN admet-144 77 27 ) ) PUNCT admet-144 77 28 ) ) PUNCT admet-144 77 29 . . PUNCT admet-144 78 1 camenisch camenisch PROPN admet-144 78 2 et et PROPN admet-144 78 3 al al PROPN admet-144 78 4 . . PROPN admet-144 78 5 admet admet PROPN admet-144 78 6 & & CCONJ admet-144 78 7 dmpk dmpk PROPN admet-144 78 8 3(1 3(1 NUM admet-144 78 9 ) ) PUNCT admet-144 78 10 ( ( PUNCT admet-144 78 11 2015 2015 NUM admet-144 78 12 ) ) PUNCT admet-144 78 13 1 1 NUM admet-144 78 14 - - SYM admet-144 78 15 14 14 NUM admet-144 78 16 6 6 NUM admet-144 78 17 fig fig NOUN admet-144 78 18 . . PUNCT admet-144 79 1 2 2 NUM admet-144 79 2 ( ( PUNCT admet-144 79 3 panel panel NOUN admet-144 79 4 d d NOUN admet-144 79 5 ) ) PUNCT admet-144 79 6 illustrates illustrate VERB admet-144 79 7 the the DET admet-144 79 8 relationship relationship NOUN admet-144 79 9 between between ADP admet-144 79 10 fnren fnren NOUN admet-144 79 11 and and CCONJ admet-144 79 12 total total ADJ admet-144 79 13 sinusoidal sinusoidal NOUN admet-144 79 14 uptake uptake ADJ admet-144 79 15 ( ( PUNCT admet-144 79 16 psinf psinf ADJ admet-144 79 17 ) ) PUNCT admet-144 79 18 for for ADP admet-144 79 19 the the DET admet-144 79 20 present present ADJ admet-144 79 21 dataset dataset NOUN admet-144 79 22 . . PUNCT admet-144 80 1 as as SCONJ admet-144 80 2 discussed discuss VERB admet-144 80 3 above above ADV admet-144 80 4 , , PUNCT admet-144 80 5 a a DET admet-144 80 6 low low ADJ admet-144 80 7 permeability permeability NOUN admet-144 80 8 is be AUX admet-144 80 9 hindering hinder VERB admet-144 80 10 hepatic hepatic ADJ admet-144 80 11 elimination elimination NOUN admet-144 80 12 pushing push VERB admet-144 80 13 drugs drug NOUN admet-144 80 14 towards towards ADP admet-144 80 15 alternative alternative ADJ admet-144 80 16 elimination elimination NOUN admet-144 80 17 routes route NOUN admet-144 80 18 ( ( PUNCT admet-144 80 19 with with ADP admet-144 80 20 decreasing decrease VERB admet-144 80 21 lipophilicity lipophilicity NOUN admet-144 80 22 plasma plasma NOUN admet-144 80 23 protein protein NOUN admet-144 80 24 binding bind VERB admet-144 80 25 usually usually ADV admet-144 80 26 decreases decrease VERB admet-144 80 27 which which PRON admet-144 80 28 would would AUX admet-144 80 29 result result VERB admet-144 80 30 in in ADP admet-144 80 31 increased increase VERB admet-144 80 32 glomerular glomerular ADJ admet-144 80 33 filtration filtration NOUN admet-144 80 34 process process NOUN admet-144 80 35 , , PUNCT admet-144 80 36 possibly possibly ADV admet-144 80 37 increased increase VERB admet-144 80 38 active active ADJ admet-144 80 39 tubular tubular ADJ admet-144 80 40 secretion secretion NOUN admet-144 80 41 and and CCONJ admet-144 80 42 less less ADJ admet-144 80 43 reabsorption reabsorption NOUN admet-144 80 44 ) ) PUNCT admet-144 81 1 [ [ X admet-144 81 2 4 4 NUM admet-144 81 3 ] ] PUNCT admet-144 81 4 . . PUNCT admet-144 82 1 beyond beyond ADP admet-144 82 2 a a DET admet-144 82 3 psinf psinf ADJ admet-144 82 4 value value NOUN admet-144 82 5 of of ADP admet-144 82 6 100 100 NUM admet-144 82 7 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 82 8 ) ) PUNCT admet-144 82 9 ) ) PUNCT admet-144 82 10 renal renal ADJ admet-144 82 11 elimination elimination NOUN admet-144 82 12 becomes become VERB admet-144 82 13 very very ADV admet-144 82 14 unlikely unlikely ADJ admet-144 82 15 . . PUNCT admet-144 83 1 consequently consequently ADV admet-144 83 2 , , PUNCT admet-144 83 3 following follow VERB admet-144 83 4 integration integration NOUN admet-144 83 5 of of ADP admet-144 83 6 the the DET admet-144 83 7 information information NOUN admet-144 83 8 from from ADP admet-144 83 9 this this PRON admet-144 83 10 and and CCONJ admet-144 83 11 the the DET admet-144 83 12 previous previous ADJ admet-144 83 13 chapter chapter NOUN admet-144 83 14 , , PUNCT admet-144 83 15 it it PRON admet-144 83 16 becomes become VERB admet-144 83 17 apparent apparent ADJ admet-144 83 18 that that SCONJ admet-144 83 19 total total ADJ admet-144 83 20 sinusoidal sinusoidal NOUN admet-144 83 21 uptake uptake ADJ admet-144 83 22 is be AUX admet-144 83 23 the the DET admet-144 83 24 predominant predominant ADJ admet-144 83 25 gatekeeper gatekeeper NOUN admet-144 83 26 between between ADP admet-144 83 27 almost almost ADV admet-144 83 28 exclusive exclusive ADJ admet-144 83 29 metabolic metabolic NOUN admet-144 83 30 hepatic hepatic ADJ admet-144 83 31 elimination elimination NOUN admet-144 83 32 ( ( PUNCT admet-144 83 33 > > X admet-144 83 34 200 200 NUM admet-144 83 35 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 83 36 ) ) PUNCT admet-144 83 37 ) ) PUNCT admet-144 83 38 , , PUNCT admet-144 83 39 mixed mixed ADJ admet-144 83 40 hepatic hepatic NOUN admet-144 83 41 ( ( PUNCT admet-144 83 42 metabolism metabolism NOUN admet-144 83 43 plus plus CCONJ admet-144 83 44 biliary biliary ADJ admet-144 83 45 secretion secretion NOUN admet-144 83 46 , , PUNCT admet-144 83 47 100 100 NUM admet-144 83 48 - - SYM admet-144 83 49 200 200 NUM admet-144 83 50 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 83 51 ) ) PUNCT admet-144 83 52 ) ) PUNCT admet-144 83 53 and and CCONJ admet-144 83 54 mixed mixed ADJ admet-144 83 55 hepatic hepatic ADJ admet-144 83 56 / / SYM admet-144 83 57 renal renal ADJ admet-144 83 58 elimination elimination NOUN admet-144 83 59 ( ( PUNCT admet-144 83 60 metabolism metabolism NOUN admet-144 83 61 plus plus CCONJ admet-144 83 62 biliary biliary ADJ admet-144 83 63 and and CCONJ admet-144 83 64 urinary urinary ADJ admet-144 83 65 secretion secretion NOUN admet-144 83 66 , , PUNCT admet-144 83 67 < < X admet-144 83 68 100 100 NUM admet-144 83 69 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 83 70 ) ) PUNCT admet-144 83 71 ) ) PUNCT admet-144 83 72 ( ( PUNCT admet-144 83 73 fig fig NOUN admet-144 83 74 . . PUNCT admet-144 83 75 5 5 NUM admet-144 83 76 ) ) PUNCT admet-144 83 77 . . PUNCT admet-144 84 1 exclusive exclusive ADJ admet-144 84 2 renal renal ADJ admet-144 84 3 clearance clearance NOUN admet-144 84 4 is be AUX admet-144 84 5 expected expect VERB admet-144 84 6 only only ADV admet-144 84 7 if if SCONJ admet-144 84 8 psinf psinf ADJ admet-144 84 9 is be AUX admet-144 84 10 approaching approach VERB admet-144 84 11 a a DET admet-144 84 12 very very ADV admet-144 84 13 low low ADJ admet-144 84 14 value value NOUN admet-144 84 15 or or CCONJ admet-144 84 16 if if SCONJ admet-144 84 17 substantial substantial ADJ admet-144 84 18 entero entero ADJ admet-144 84 19 - - PUNCT admet-144 84 20 hepatic hepatic NOUN admet-144 84 21 circulation circulation NOUN admet-144 84 22 is be AUX admet-144 84 23 taking take VERB admet-144 84 24 place place NOUN admet-144 84 25 . . PUNCT admet-144 85 1 yet yet ADV admet-144 85 2 , , PUNCT admet-144 85 3 renal renal ADJ admet-144 85 4 excretion excretion NOUN admet-144 85 5 might might AUX admet-144 85 6 become become VERB admet-144 85 7 the the DET admet-144 85 8 predominant predominant ADJ admet-144 85 9 elimination elimination NOUN admet-144 85 10 pathway pathway NOUN admet-144 85 11 for for ADP admet-144 85 12 low low ADJ admet-144 85 13 permeable permeable ADJ admet-144 85 14 compounds compound NOUN admet-144 85 15 with with ADP admet-144 85 16 about about ADP admet-144 85 17 psinf psinf ADJ admet-144 85 18 < < X admet-144 85 19 30 30 NUM admet-144 85 20 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 85 21 ) ) PUNCT admet-144 85 22 ( ( PUNCT admet-144 85 23 fig fig NOUN admet-144 85 24 . . PUNCT admet-144 86 1 2 2 NUM admet-144 86 2 , , PUNCT admet-144 86 3 panel panel NOUN admet-144 86 4 d d NOUN admet-144 86 5 ) ) PUNCT admet-144 86 6 . . PUNCT admet-144 87 1 for for ADP admet-144 87 2 compounds compound NOUN admet-144 87 3 with with ADP admet-144 87 4 sinusoidal sinusoidal NOUN admet-144 87 5 uptake uptake ADJ admet-144 87 6 between between ADP admet-144 87 7 30 30 NUM admet-144 87 8 - - SYM admet-144 87 9 60 60 NUM admet-144 87 10 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 87 11 ) ) PUNCT admet-144 87 12 , , PUNCT admet-144 87 13 mixed mixed ADJ admet-144 87 14 urinary urinary ADJ admet-144 87 15 / / SYM admet-144 87 16 biliary biliary ADJ admet-144 87 17 elimination elimination NOUN admet-144 87 18 seems seem VERB admet-144 87 19 to to PART admet-144 87 20 be be AUX admet-144 87 21 the the DET admet-144 87 22 most most ADV admet-144 87 23 probable probable ADJ admet-144 87 24 clearance clearance NOUN admet-144 87 25 pathway pathway NOUN admet-144 87 26 . . PUNCT admet-144 88 1 consequently consequently ADV admet-144 88 2 , , PUNCT admet-144 88 3 the the DET admet-144 88 4 relationship relationship NOUN admet-144 88 5 between between ADP admet-144 88 6 psinf psinf ADJ admet-144 88 7 , , PUNCT admet-144 88 8 pas pas NOUN admet-144 88 9 and and CCONJ admet-144 88 10 fnsec fnsec PROPN admet-144 88 11 as as SCONJ admet-144 88 12 shown show VERB admet-144 88 13 in in ADP admet-144 88 14 figure figure NOUN admet-144 88 15 2 2 NUM admet-144 88 16 ( ( PUNCT admet-144 88 17 panel panel NOUN admet-144 88 18 b b X admet-144 88 19 ) ) PUNCT admet-144 88 20 likely likely ADV admet-144 88 21 needs need VERB admet-144 88 22 to to PART admet-144 88 23 be be AUX admet-144 88 24 interpreted interpret VERB admet-144 88 25 as as ADP admet-144 88 26 a a DET admet-144 88 27 bell bell NOUN admet-144 88 28 - - PUNCT admet-144 88 29 shaped shape VERB admet-144 88 30 curve curve NOUN admet-144 88 31 with with ADP admet-144 88 32 a a DET admet-144 88 33 psinf psinf NOUN admet-144 88 34 , , PUNCT admet-144 88 35 pas pas NOUN admet-144 88 36 maximum maximum NOUN admet-144 88 37 at at ADP admet-144 88 38 around around ADV admet-144 88 39 30 30 NUM admet-144 88 40 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 88 41 ) ) PUNCT admet-144 88 42 ( ( PUNCT admet-144 88 43 maximal maximal ADJ admet-144 88 44 fnsec fnsec NOUN admet-144 88 45 β‰ˆ β‰ˆ PROPN admet-144 88 46 0.6 0.6 NUM admet-144 88 47 - - SYM admet-144 88 48 0.7 0.7 NUM admet-144 88 49 ) ) PUNCT admet-144 88 50 . . PUNCT admet-144 89 1 figure figure NOUN admet-144 89 2 5 5 NUM admet-144 89 3 . . PUNCT admet-144 89 4 schematic schematic ADJ admet-144 89 5 illustration illustration NOUN admet-144 89 6 of of ADP admet-144 89 7 the the DET admet-144 89 8 change change NOUN admet-144 89 9 in in ADP admet-144 89 10 elimination elimination NOUN admet-144 89 11 route route NOUN admet-144 89 12 as as ADP admet-144 89 13 a a DET admet-144 89 14 function function NOUN admet-144 89 15 of of ADP admet-144 89 16 sinusoidal sinusoidal NOUN admet-144 89 17 uptake uptake ADJ admet-144 89 18 ( ( PUNCT admet-144 89 19 psinf psinf ADJ admet-144 89 20 ) ) PUNCT admet-144 89 21 . . PUNCT admet-144 90 1 fnmet fnmet PROPN admet-144 90 2 , , PUNCT admet-144 90 3 fnren fnren PROPN admet-144 90 4 and and CCONJ admet-144 90 5 fnsec fnsec PROPN admet-144 90 6 denote denote VERB admet-144 90 7 the the DET admet-144 90 8 fractional fractional ADJ admet-144 90 9 contributions contribution NOUN admet-144 90 10 of of ADP admet-144 90 11 ( ( PUNCT admet-144 90 12 hepatic hepatic ADJ admet-144 90 13 ) ) PUNCT admet-144 90 14 metabolic metabolic NOUN admet-144 90 15 , , PUNCT admet-144 90 16 urinary urinary ADJ admet-144 90 17 and and CCONJ admet-144 90 18 biliary biliary ADJ admet-144 90 19 elimination elimination NOUN admet-144 90 20 to to ADP admet-144 90 21 overall overall ADJ admet-144 90 22 clearance clearance NOUN admet-144 90 23 , , PUNCT admet-144 90 24 respectively respectively ADV admet-144 90 25 . . PUNCT admet-144 91 1 above above ADP admet-144 91 2 a a DET admet-144 91 3 psinf psinf ADJ admet-144 91 4 threshold threshold NOUN admet-144 91 5 of of ADP admet-144 91 6 about about ADV admet-144 91 7 60 60 NUM admet-144 91 8 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 91 9 ) ) PUNCT admet-144 91 10 liver liver NOUN admet-144 91 11 is be AUX admet-144 91 12 the the DET admet-144 91 13 expected expect VERB admet-144 91 14 primary primary ADJ admet-144 91 15 clearance clearance NOUN admet-144 91 16 organ organ NOUN admet-144 91 17 whereas whereas SCONJ admet-144 91 18 below below ADP admet-144 91 19 30 30 NUM admet-144 91 20 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 91 21 ) ) PUNCT admet-144 91 22 renal renal ADJ admet-144 91 23 elimination elimination NOUN admet-144 91 24 is be AUX admet-144 91 25 likely likely ADV admet-144 91 26 predominant predominant ADJ admet-144 91 27 . . PUNCT admet-144 92 1 extended extended ADJ admet-144 92 2 clearance clearance NOUN admet-144 92 3 concept concept NOUN admet-144 92 4 classification classification NOUN admet-144 92 5 system system NOUN admet-144 92 6 the the DET admet-144 92 7 extended extended ADJ admet-144 92 8 clearance clearance NOUN admet-144 92 9 concept concept NOUN admet-144 92 10 ( ( PUNCT admet-144 92 11 ecc ecc PROPN admet-144 92 12 ) ) PUNCT admet-144 92 13 is be AUX admet-144 92 14 the the DET admet-144 92 15 intangible intangible ADJ admet-144 92 16 attempt attempt NOUN admet-144 92 17 to to PART admet-144 92 18 complete complete VERB admet-144 92 19 the the DET admet-144 92 20 principles principle NOUN admet-144 92 21 of of ADP admet-144 92 22 the the DET admet-144 92 23 extended extended ADJ admet-144 92 24 clearance clearance NOUN admet-144 92 25 model model NOUN admet-144 92 26 ( ( PUNCT admet-144 92 27 fig fig NOUN admet-144 92 28 . . NOUN admet-144 93 1 1 1 NUM admet-144 93 2 ) ) PUNCT admet-144 93 3 with with ADP admet-144 93 4 the the DET admet-144 93 5 gatekeeping gatekeepe VERB admet-144 93 6 role role NOUN admet-144 93 7 of of ADP admet-144 93 8 sinusoidal sinusoidal NOUN admet-144 93 9 influx influx NOUN admet-144 93 10 as as SCONJ admet-144 93 11 discussed discuss VERB admet-144 93 12 above above ADV admet-144 93 13 ( ( PUNCT admet-144 93 14 fig fig NOUN admet-144 93 15 . . PUNCT admet-144 93 16 5 5 NUM admet-144 93 17 ) ) PUNCT admet-144 94 1 to to PART admet-144 94 2 allow allow VERB admet-144 94 3 prediction prediction NOUN admet-144 94 4 of of ADP admet-144 94 5 in in ADP admet-144 94 6 vivo vivo ADJ admet-144 94 7 pharmacokinetic pharmacokinetic ADJ admet-144 94 8 performance performance NOUN admet-144 94 9 of of ADP admet-144 94 10 drugs drug NOUN admet-144 94 11 from from ADP admet-144 94 12 in in ADP admet-144 94 13 vitro vitro X admet-144 94 14 permeability permeability NOUN admet-144 94 15 and and CCONJ admet-144 94 16 metabolism metabolism NOUN admet-144 94 17 data datum NOUN admet-144 94 18 as as SCONJ admet-144 94 19 illustrated illustrate VERB admet-144 94 20 in in ADP admet-144 94 21 fig fig NOUN admet-144 94 22 . . PUNCT admet-144 95 1 6 6 NUM admet-144 95 2 . . X admet-144 95 3 drugs drug NOUN admet-144 95 4 with with ADP admet-144 95 5 a a DET admet-144 95 6 high high ADJ admet-144 95 7 apparent apparent ADJ admet-144 95 8 hepatic hepatic ADJ admet-144 95 9 intrinsic intrinsic ADJ admet-144 95 10 clearance clearance NOUN admet-144 95 11 are be AUX admet-144 95 12 removed remove VERB admet-144 95 13 from from ADP admet-144 95 14 the the DET admet-144 95 15 blood blood NOUN admet-144 95 16 essentially essentially ADV admet-144 95 17 as as ADV admet-144 95 18 fast fast ADV admet-144 95 19 as as SCONJ admet-144 95 20 they they PRON admet-144 95 21 can can AUX admet-144 95 22 be be AUX admet-144 95 23 delivered deliver VERB admet-144 95 24 to to ADP admet-144 95 25 the the DET admet-144 95 26 liver liver NOUN admet-144 95 27 , , PUNCT admet-144 95 28 i.e. i.e. X admet-144 95 29 independent independent ADJ admet-144 95 30 of of ADP admet-144 95 31 protein protein NOUN admet-144 95 32 binding bind VERB admet-144 95 33 and and CCONJ admet-144 95 34 intrinsic intrinsic ADJ admet-144 95 35 enzyme enzyme NOUN admet-144 95 36 and and CCONJ admet-144 95 37 canalicular canalicular ADJ admet-144 95 38 efflux efflux NOUN admet-144 95 39 transporter transporter NOUN admet-144 95 40 activities activity NOUN admet-144 95 41 . . PUNCT admet-144 96 1 therefore therefore ADV admet-144 96 2 , , PUNCT admet-144 96 3 the the DET admet-144 96 4 elimination elimination NOUN admet-144 96 5 of of ADP admet-144 96 6 such such ADJ admet-144 96 7 drugs drug NOUN admet-144 96 8 is be AUX admet-144 96 9 highly highly ADV admet-144 96 10 dependent dependent ADJ admet-144 96 11 upon upon SCONJ admet-144 96 12 liver liver NOUN admet-144 96 13 blood blood NOUN admet-144 96 14 flow flow NOUN admet-144 96 15 and and CCONJ admet-144 96 16 the the DET admet-144 96 17 inherent inherent ADJ admet-144 96 18 ability ability NOUN admet-144 96 19 to to PART admet-144 96 20 cross cross VERB admet-144 96 21 the the DET admet-144 96 22 sinusoidal sinusoidal ADJ admet-144 96 23 membrane membrane NOUN admet-144 96 24 rapidly rapidly ADV admet-144 96 25 . . PUNCT admet-144 97 1 consequently consequently ADV admet-144 97 2 , , PUNCT admet-144 97 3 according accord VERB admet-144 97 4 to to ADP admet-144 97 5 the the DET admet-144 97 6 well well ADV admet-144 97 7 - - PUNCT admet-144 97 8 stirred stir VERB admet-144 97 9 liver liver NOUN admet-144 97 10 model model NOUN admet-144 97 11 , , PUNCT admet-144 97 12 a a DET admet-144 97 13 compound compound NOUN admet-144 97 14 can can AUX admet-144 97 15 be be AUX admet-144 97 16 ranked rank VERB admet-144 97 17 as as ADP admet-144 97 18 highly highly ADV admet-144 97 19 permeable permeable ADJ admet-144 97 20 if if SCONJ admet-144 97 21 admet admet PROPN admet-144 97 22 & & CCONJ admet-144 97 23 dmpk dmpk PROPN admet-144 97 24 3(1 3(1 NUM admet-144 97 25 ) ) PUNCT admet-144 97 26 ( ( PUNCT admet-144 97 27 2015 2015 NUM admet-144 97 28 ) ) PUNCT admet-144 97 29 1 1 NUM admet-144 97 30 - - SYM admet-144 97 31 14 14 NUM admet-144 97 32 extended extended ADJ admet-144 97 33 clearance clearance NOUN admet-144 97 34 concept concept NOUN admet-144 97 35 classification classification NOUN admet-144 97 36 system system NOUN admet-144 97 37 ( ( PUNCT admet-144 97 38 ecccs ecccs NOUN admet-144 97 39 ) ) PUNCT admet-144 97 40 doi doi NOUN admet-144 97 41 : : PUNCT admet-144 97 42 10.5599 10.5599 NUM admet-144 97 43 / / SYM admet-144 97 44 admet.3.1.144 admet.3.1.144 PROPN admet-144 97 45 7 7 NUM admet-144 97 46 clh clh NOUN admet-144 97 47 , , PUNCT admet-144 97 48 int int NOUN admet-144 97 49 = = SYM admet-144 97 50 psinf psinf NOUN admet-144 97 51 , , PUNCT admet-144 97 52 pas pas PROPN admet-144 97 53 > > PUNCT admet-144 97 54 > > X admet-144 97 55 qh qh PROPN admet-144 97 56 ( ( PUNCT admet-144 97 57 eq eq NOUN admet-144 97 58 . . PUNCT admet-144 98 1 ( ( PUNCT admet-144 98 2 1 1 NUM admet-144 98 3 ) ) PUNCT admet-144 98 4 and and CCONJ admet-144 98 5 eq eq NOUN admet-144 98 6 . . PUNCT admet-144 99 1 ( ( PUNCT admet-144 99 2 2 2 NUM admet-144 99 3 ) ) PUNCT admet-144 99 4 ) ) PUNCT admet-144 99 5 . . PUNCT admet-144 100 1 from from ADP admet-144 100 2 above above ADP admet-144 100 3 discussion discussion NOUN admet-144 100 4 it it PRON admet-144 100 5 is be AUX admet-144 100 6 evident evident ADJ admet-144 100 7 that that SCONJ admet-144 100 8 a a DET admet-144 100 9 ( ( PUNCT admet-144 100 10 passive passive ADJ admet-144 100 11 ) ) PUNCT admet-144 100 12 sinusoidal sinusoidal ADJ admet-144 100 13 permeability permeability NOUN admet-144 100 14 above above ADP admet-144 100 15 60 60 NUM admet-144 100 16 ml/(minΒ·kg ml/(minΒ·kg NUM admet-144 100 17 ) ) PUNCT admet-144 100 18 results result NOUN admet-144 100 19 in in ADP admet-144 100 20 an an DET admet-144 100 21 almost almost ADV admet-144 100 22 complete complete ADJ admet-144 100 23 hepatic hepatic ADJ admet-144 100 24 clearance clearance NOUN admet-144 100 25 ( ( PUNCT admet-144 100 26 fig fig NOUN admet-144 100 27 . . PUNCT admet-144 101 1 2 2 NUM admet-144 101 2 , , PUNCT admet-144 101 3 panel panel NOUN admet-144 101 4 c c NOUN admet-144 101 5 and and CCONJ admet-144 101 6 fig fig NOUN admet-144 101 7 . . PUNCT admet-144 102 1 5 5 NUM admet-144 102 2 ) ) PUNCT admet-144 102 3 . . PUNCT admet-144 103 1 thus thus ADV admet-144 103 2 , , PUNCT admet-144 103 3 a a DET admet-144 103 4 compound compound NOUN admet-144 103 5 can can AUX admet-144 103 6 be be AUX admet-144 103 7 ranked rank VERB admet-144 103 8 as as ADP admet-144 103 9 highly highly ADV admet-144 103 10 permeable permeable ADJ admet-144 103 11 if if SCONJ admet-144 103 12 psinf psinf ADJ admet-144 103 13 , , PUNCT admet-144 103 14 pas pas X admet-144 103 15 β‰₯ β‰₯ NOUN admet-144 103 16 3 3 NUM admet-144 103 17 - - ADJ admet-144 103 18 fold fold ADJ admet-144 103 19 qh qh NOUN admet-144 103 20 , , PUNCT admet-144 103 21 a a DET admet-144 103 22 threshold threshold NOUN admet-144 103 23 substantiating substantiate VERB admet-144 103 24 the the DET admet-144 103 25 conceptual conceptual ADJ admet-144 103 26 approximation approximation NOUN admet-144 103 27 psinf psinf NOUN admet-144 103 28 β‰ˆ β‰ˆ PROPN admet-144 103 29 pseff pseff NOUN admet-144 103 30 β‰ˆ β‰ˆ PROPN admet-144 103 31 psinf psinf NOUN admet-144 103 32 , , PUNCT admet-144 103 33 pas pa NOUN admet-144 103 34 pertinent pertinent NOUN admet-144 103 35 to to ADP admet-144 103 36 all all DET admet-144 103 37 compounds compound NOUN admet-144 103 38 identified identify VERB admet-144 103 39 to to PART admet-144 103 40 be be AUX admet-144 103 41 hepatic hepatic ADJ admet-144 103 42 uptake uptake ADJ admet-144 103 43 transporter transporter NOUN admet-144 103 44 substrates substrate NOUN admet-144 103 45 besides besides SCONJ admet-144 103 46 demonstrating demonstrate VERB admet-144 103 47 a a DET admet-144 103 48 high high ADJ admet-144 103 49 intrinsic intrinsic ADJ admet-144 103 50 permeation permeation NOUN admet-144 103 51 potential potential NOUN admet-144 103 52 across across ADP admet-144 103 53 the the DET admet-144 103 54 sinusoidal sinusoidal ADJ admet-144 103 55 membrane membrane NOUN admet-144 103 56 of of ADP admet-144 103 57 hepatocytes hepatocyte NOUN admet-144 103 58 . . PUNCT admet-144 104 1 hence hence ADV admet-144 104 2 , , PUNCT admet-144 104 3 it it PRON admet-144 104 4 becomes become VERB admet-144 104 5 evident evident ADJ admet-144 104 6 that that SCONJ admet-144 104 7 uptake uptake VERB admet-144 104 8 transporter transporter NOUN admet-144 104 9 effects effect NOUN admet-144 104 10 for for ADP admet-144 104 11 highly highly ADV admet-144 104 12 permeable permeable ADJ admet-144 104 13 compounds compound NOUN admet-144 104 14 are be AUX admet-144 104 15 minimally minimally ADV admet-144 104 16 contributing contribute VERB admet-144 104 17 to to ADP admet-144 104 18 overall overall ADJ admet-144 104 19 hepatic hepatic ADJ admet-144 104 20 clearance clearance NOUN admet-144 104 21 while while SCONJ admet-144 104 22 they they PRON admet-144 104 23 are be AUX admet-144 104 24 expected expect VERB admet-144 104 25 to to PART admet-144 104 26 become become VERB admet-144 104 27 important important ADJ admet-144 104 28 / / SYM admet-144 104 29 predominant predominant NOUN admet-144 104 30 for for ADP admet-144 104 31 the the DET admet-144 104 32 hepatic hepatic ADJ admet-144 104 33 clearance clearance NOUN admet-144 104 34 of of ADP admet-144 104 35 lower low ADJ admet-144 104 36 permeable permeable ADJ admet-144 104 37 compounds compound NOUN admet-144 104 38 . . PUNCT admet-144 105 1 applying apply VERB admet-144 105 2 this this DET admet-144 105 3 fundamental fundamental ADJ admet-144 105 4 relationship relationship NOUN admet-144 105 5 , , PUNCT admet-144 105 6 the the DET admet-144 105 7 19 19 NUM admet-144 105 8 compounds compound NOUN admet-144 105 9 in in ADP admet-144 105 10 our our PRON admet-144 105 11 dataset dataset NOUN admet-144 105 12 were be AUX admet-144 105 13 assigned assign VERB admet-144 105 14 to to ADP admet-144 105 15 the the DET admet-144 105 16 four four NUM admet-144 105 17 different different ADJ admet-144 105 18 ecc ecc PROPN admet-144 105 19 classes class NOUN admet-144 105 20 as as SCONJ admet-144 105 21 summarized summarize VERB admet-144 105 22 in in ADP admet-144 105 23 table table NOUN admet-144 105 24 1 1 NUM admet-144 105 25 . . PUNCT admet-144 106 1 figure figure VERB admet-144 106 2 6 6 NUM admet-144 106 3 . . PUNCT admet-144 107 1 predominant predominant ADJ admet-144 107 2 routes route NOUN admet-144 107 3 of of ADP admet-144 107 4 drug drug NOUN admet-144 107 5 elimination elimination NOUN admet-144 107 6 and and CCONJ admet-144 107 7 potential potential ADJ admet-144 107 8 transporter transporter NOUN admet-144 107 9 effects effect NOUN admet-144 107 10 on on ADP admet-144 107 11 ( ( PUNCT admet-144 107 12 hepatic hepatic ADJ admet-144 107 13 ) ) PUNCT admet-144 107 14 drug drug NOUN admet-144 107 15 disposition disposition NOUN admet-144 107 16 according accord VERB admet-144 107 17 to to ADP admet-144 107 18 the the DET admet-144 107 19 extended extended ADJ admet-144 107 20 clearance clearance NOUN admet-144 107 21 concept concept NOUN admet-144 107 22 classification classification NOUN admet-144 107 23 system system NOUN admet-144 107 24 ( ( PUNCT admet-144 107 25 ecccs ecccs PROPN admet-144 107 26 ) ) PUNCT admet-144 107 27 . . PUNCT admet-144 108 1 thresholds threshold NOUN admet-144 108 2 as as SCONJ admet-144 108 3 defined define VERB admet-144 108 4 by by ADP admet-144 108 5 the the DET admet-144 108 6 biopharmaceutics biopharmaceutics NOUN admet-144 108 7 drug drug NOUN admet-144 108 8 disposition disposition NOUN admet-144 108 9 classification classification NOUN admet-144 108 10 system system NOUN admet-144 108 11 ( ( PUNCT admet-144 108 12 bddcs bddcs NOUN admet-144 108 13 ) ) PUNCT admet-144 108 14 are be AUX admet-144 108 15 provided provide VERB admet-144 108 16 for for ADP admet-144 108 17 comparative comparative ADJ admet-144 108 18 reasons reason NOUN admet-144 108 19 also also ADV admet-144 108 20 [ [ X admet-144 108 21 1,8 1,8 NUM admet-144 108 22 ] ] X admet-144 108 23 . . PUNCT admet-144 109 1 taking take VERB admet-144 109 2 all all PRON admet-144 109 3 above above ADP admet-144 109 4 principles principle NOUN admet-144 109 5 into into ADP admet-144 109 6 account account NOUN admet-144 109 7 it it PRON admet-144 109 8 is be AUX admet-144 109 9 appropriate appropriate ADJ admet-144 109 10 to to PART admet-144 109 11 conclude conclude VERB admet-144 109 12 that that SCONJ admet-144 109 13 the the DET admet-144 109 14 major major ADJ admet-144 109 15 route route NOUN admet-144 109 16 of of ADP admet-144 109 17 elimination elimination NOUN admet-144 109 18 for for ADP admet-144 109 19 ecc ecc PROPN admet-144 109 20 class class NOUN admet-144 109 21 3 3 NUM admet-144 109 22 and and CCONJ admet-144 109 23 4 4 NUM admet-144 109 24 compounds compound NOUN admet-144 109 25 is be AUX admet-144 109 26 renal renal ADJ admet-144 109 27 and and CCONJ admet-144 109 28 biliary biliary ADJ admet-144 109 29 excretion excretion NOUN admet-144 109 30 of of ADP admet-144 109 31 unchanged unchanged ADJ admet-144 109 32 drug drug NOUN admet-144 109 33 whereas whereas SCONJ admet-144 109 34 metabolism metabolism NOUN admet-144 109 35 is be AUX admet-144 109 36 the the DET admet-144 109 37 predominant predominant ADJ admet-144 109 38 elimination elimination NOUN admet-144 109 39 pathway pathway NOUN admet-144 109 40 for for ADP admet-144 109 41 ecc ecc PROPN admet-144 109 42 class class NOUN admet-144 109 43 1 1 NUM admet-144 109 44 and and CCONJ admet-144 109 45 2 2 NUM admet-144 109 46 compounds compound NOUN admet-144 109 47 as as SCONJ admet-144 109 48 previously previously ADV admet-144 109 49 concluded conclude VERB admet-144 109 50 by by ADP admet-144 109 51 others other NOUN admet-144 109 52 also also ADV admet-144 109 53 [ [ X admet-144 109 54 8 8 NUM admet-144 109 55 ] ] PUNCT admet-144 109 56 . . PUNCT admet-144 110 1 however however ADV admet-144 110 2 , , PUNCT admet-144 110 3 ecc ecc PROPN admet-144 110 4 allows allow VERB admet-144 110 5 a a DET admet-144 110 6 compound compound NOUN admet-144 110 7 classification classification NOUN admet-144 110 8 of of ADP admet-144 110 9 drug drug NOUN admet-144 110 10 molecules molecule NOUN admet-144 110 11 based base VERB admet-144 110 12 on on ADP admet-144 110 13 their their PRON admet-144 110 14 in in X admet-144 110 15 vitro vitro X admet-144 110 16 determined determined ADJ admet-144 110 17 ( ( PUNCT admet-144 110 18 hepatic hepatic ADJ admet-144 110 19 ) ) PUNCT admet-144 110 20 clearance clearance NOUN admet-144 110 21 parameters parameter NOUN admet-144 110 22 in in ADP admet-144 110 23 contrast contrast NOUN admet-144 110 24 to to ADP admet-144 110 25 the the DET admet-144 110 26 biopharmaceutics biopharmaceutics NOUN admet-144 110 27 drug drug NOUN admet-144 110 28 disposition disposition NOUN admet-144 110 29 classification classification NOUN admet-144 110 30 system system NOUN admet-144 110 31 ( ( PUNCT admet-144 110 32 bddcs bddcs NOUN admet-144 110 33 ) ) PUNCT admet-144 110 34 which which PRON admet-144 110 35 allocates allocate VERB admet-144 110 36 drugs drug NOUN admet-144 110 37 into into ADP admet-144 110 38 four four NUM admet-144 110 39 classes class NOUN admet-144 110 40 according accord VERB admet-144 110 41 to to ADP admet-144 110 42 their their PRON admet-144 110 43 in in ADP admet-144 110 44 vivo vivo ADJ admet-144 110 45 metabolism metabolism NOUN admet-144 110 46 and and CCONJ admet-144 110 47 solubility solubility NOUN admet-144 110 48 potential potential NOUN admet-144 110 49 . . PUNCT admet-144 111 1 both both DET admet-144 111 2 concepts concept NOUN admet-144 111 3 are be AUX admet-144 111 4 closely closely ADV admet-144 111 5 related relate VERB admet-144 111 6 and and CCONJ admet-144 111 7 have have VERB admet-144 111 8 in in ADP admet-144 111 9 common common ADJ admet-144 111 10 that that SCONJ admet-144 111 11 they they PRON admet-144 111 12 recognize recognize VERB admet-144 111 13 that that SCONJ admet-144 111 14 the the DET admet-144 111 15 fundamental fundamental ADJ admet-144 111 16 parameter parameter NOUN admet-144 111 17 controlling control VERB admet-144 111 18 ( ( PUNCT admet-144 111 19 hepatic hepatic ADJ admet-144 111 20 ) ) PUNCT admet-144 111 21 drug drug NOUN admet-144 111 22 disposition disposition NOUN admet-144 111 23 is be AUX admet-144 111 24 the the DET admet-144 111 25 compound compound NOUN admet-144 111 26 class class NOUN admet-144 111 27 - - PUNCT admet-144 111 28 dependent dependent ADJ admet-144 111 29 interplay interplay NOUN admet-144 111 30 between between ADP admet-144 111 31 transporters transporter NOUN admet-144 111 32 , , PUNCT admet-144 111 33 enzymes enzyme NOUN admet-144 111 34 and and CCONJ admet-144 111 35 membrane membrane NOUN admet-144 111 36 permeability permeability NOUN admet-144 111 37 . . PUNCT admet-144 112 1 both both DET admet-144 112 2 systems system NOUN admet-144 112 3 provide provide VERB admet-144 112 4 a a DET admet-144 112 5 similar similar ADJ admet-144 112 6 rational rational NOUN admet-144 112 7 on on ADP admet-144 112 8 the the DET admet-144 112 9 predominant predominant ADJ admet-144 112 10 routes route NOUN admet-144 112 11 of of ADP admet-144 112 12 drug drug NOUN admet-144 112 13 elimination elimination NOUN admet-144 112 14 and and CCONJ admet-144 112 15 the the DET admet-144 112 16 potential potential ADJ admet-144 112 17 effect effect NOUN admet-144 112 18 of of ADP admet-144 112 19 transporters transporter NOUN admet-144 112 20 on on ADP admet-144 112 21 ( ( PUNCT admet-144 112 22 hepatic hepatic ADJ admet-144 112 23 ) ) PUNCT admet-144 112 24 drug drug NOUN admet-144 112 25 disposition disposition NOUN admet-144 112 26 as as SCONJ admet-144 112 27 illustrated illustrate VERB admet-144 112 28 in in ADP admet-144 112 29 fig fig NOUN admet-144 112 30 . . PUNCT admet-144 113 1 6 6 NUM admet-144 113 2 . . PUNCT admet-144 113 3 yet yet ADV admet-144 113 4 , , PUNCT admet-144 113 5 assignment assignment NOUN admet-144 113 6 into into ADP admet-144 113 7 bddcs bddcs PROPN admet-144 113 8 relies rely VERB admet-144 113 9 on on ADP admet-144 113 10 clinical clinical ADJ admet-144 113 11 elimination elimination NOUN admet-144 113 12 information information NOUN admet-144 113 13 and and CCONJ admet-144 113 14 is be AUX admet-144 113 15 therefore therefore ADV admet-144 113 16 not not PART admet-144 113 17 really really ADV admet-144 113 18 applicable applicable ADJ admet-144 113 19 for for ADP admet-144 113 20 early early ADJ admet-144 113 21 drug drug NOUN admet-144 113 22 development development NOUN admet-144 113 23 . . PUNCT admet-144 114 1 camenisch camenisch PROPN admet-144 114 2 et et PROPN admet-144 114 3 al al PROPN admet-144 114 4 . . PROPN admet-144 114 5 admet admet PROPN admet-144 114 6 & & CCONJ admet-144 114 7 dmpk dmpk PROPN admet-144 114 8 3(1 3(1 NUM admet-144 114 9 ) ) PUNCT admet-144 114 10 ( ( PUNCT admet-144 114 11 2015 2015 NUM admet-144 114 12 ) ) PUNCT admet-144 114 13 1 1 NUM admet-144 114 14 - - SYM admet-144 114 15 14 14 NUM admet-144 114 16 8 8 NUM admet-144 114 17 ecc ecc NOUN admet-144 114 18 and and CCONJ admet-144 114 19 ivive ivive VERB admet-144 114 20 the the DET admet-144 114 21 correlation correlation NOUN admet-144 114 22 between between ADP admet-144 114 23 the the DET admet-144 114 24 in in ADV admet-144 114 25 vitro vitro X admet-144 114 26 predicted predict VERB admet-144 114 27 ( ( PUNCT admet-144 114 28 clh clh NOUN admet-144 114 29 , , PUNCT admet-144 114 30 pred pre VERB admet-144 114 31 ) ) PUNCT admet-144 114 32 and and CCONJ admet-144 114 33 in in ADP admet-144 114 34 vivo vivo NOUN admet-144 114 35 observed observe VERB admet-144 114 36 ( ( PUNCT admet-144 114 37 clh clh NOUN admet-144 114 38 , , PUNCT admet-144 114 39 obs obs PROPN admet-144 114 40 ) ) PUNCT admet-144 114 41 hepatic hepatic ADJ admet-144 114 42 clearances clearance NOUN admet-144 114 43 for for ADP admet-144 114 44 our our PRON admet-144 114 45 dataset dataset NOUN admet-144 114 46 based base VERB admet-144 114 47 on on ADP admet-144 114 48 the the DET admet-144 114 49 mechanistic mechanistic ADJ admet-144 114 50 in in ADP admet-144 114 51 vitro vitro NOUN admet-144 114 52 - - PUNCT admet-144 114 53 in in ADP admet-144 114 54 vivo vivo ADJ admet-144 114 55 extrapolation extrapolation NOUN admet-144 114 56 ( ( PUNCT admet-144 114 57 ivive ivive ADJ admet-144 114 58 ) ) PUNCT admet-144 114 59 method method NOUN admet-144 114 60 represented represent VERB admet-144 114 61 by by ADP admet-144 114 62 eq eq PROPN admet-144 114 63 . . PUNCT admet-144 115 1 ( ( PUNCT admet-144 115 2 1 1 NUM admet-144 115 3 ) ) PUNCT admet-144 115 4 and and CCONJ admet-144 115 5 eq eq NOUN admet-144 115 6 . . PUNCT admet-144 116 1 ( ( PUNCT admet-144 116 2 2 2 X admet-144 116 3 ) ) PUNCT admet-144 116 4 is be AUX admet-144 116 5 illustrated illustrate VERB admet-144 116 6 in in ADP admet-144 116 7 fig fig NOUN admet-144 116 8 . . PUNCT admet-144 117 1 7 7 NUM admet-144 117 2 ( ( PUNCT admet-144 117 3 panel panel NOUN admet-144 117 4 a a NOUN admet-144 117 5 ) ) PUNCT admet-144 117 6 . . PUNCT admet-144 118 1 the the DET admet-144 118 2 approach approach NOUN admet-144 118 3 reveals reveal VERB admet-144 118 4 an an DET admet-144 118 5 excellent excellent ADJ admet-144 118 6 correlation correlation NOUN admet-144 118 7 with with ADP admet-144 118 8 11 11 NUM admet-144 118 9 out out ADP admet-144 118 10 of of ADP admet-144 118 11 18 18 NUM admet-144 118 12 drugs drug NOUN admet-144 118 13 predicted predict VERB admet-144 118 14 within within ADP admet-144 118 15 two two NUM admet-144 118 16 - - PUNCT admet-144 118 17 fold fold ADJ admet-144 118 18 deviation deviation NOUN admet-144 118 19 from from ADP admet-144 118 20 the the DET admet-144 118 21 clinically clinically ADV admet-144 118 22 observed observe VERB admet-144 118 23 value value NOUN admet-144 118 24 . . PUNCT admet-144 119 1 the the DET admet-144 119 2 prediction prediction NOUN admet-144 119 3 accuracy accuracy NOUN admet-144 119 4 in in ADP admet-144 119 5 terms term NOUN admet-144 119 6 of of ADP admet-144 119 7 average average ADJ admet-144 119 8 fold fold ADJ admet-144 119 9 error error NOUN admet-144 119 10 ( ( PUNCT admet-144 119 11 afe afe NOUN admet-144 119 12 ) ) PUNCT admet-144 119 13 and and CCONJ admet-144 119 14 geometric geometric ADJ admet-144 119 15 mean mean NOUN admet-144 119 16 fold fold NOUN admet-144 119 17 error error NOUN admet-144 119 18 ( ( PUNCT admet-144 119 19 gmfe gmfe NOUN admet-144 119 20 ) ) PUNCT admet-144 119 21 was be AUX admet-144 119 22 0.92 0.92 NUM admet-144 119 23 and and CCONJ admet-144 119 24 1.55 1.55 NUM admet-144 119 25 , , PUNCT admet-144 119 26 respectively respectively ADV admet-144 119 27 . . PUNCT admet-144 120 1 present present ADJ admet-144 120 2 results result NOUN admet-144 120 3 demonstrate demonstrate VERB admet-144 120 4 that that SCONJ admet-144 120 5 the the DET admet-144 120 6 extended extended ADJ admet-144 120 7 clearance clearance NOUN admet-144 120 8 concept concept NOUN admet-144 120 9 model model NOUN admet-144 120 10 is be AUX admet-144 120 11 by by ADP admet-144 120 12 far far ADV admet-144 120 13 exceeding exceed VERB admet-144 120 14 the the DET admet-144 120 15 accuracy accuracy NOUN admet-144 120 16 and and CCONJ admet-144 120 17 performance performance NOUN admet-144 120 18 of of ADP admet-144 120 19 other other ADJ admet-144 120 20 ivive ivive ADJ admet-144 120 21 prediction prediction NOUN admet-144 120 22 methods method NOUN admet-144 120 23 for for ADP admet-144 120 24 hepatic hepatic ADJ admet-144 120 25 clearance clearance NOUN admet-144 120 26 based base VERB admet-144 120 27 only only ADV admet-144 120 28 on on ADV admet-144 120 29 in in ADP admet-144 120 30 vitro vitro X admet-144 120 31 metabolism metabolism NOUN admet-144 120 32 ( ( PUNCT admet-144 120 33 fig fig NOUN admet-144 120 34 . . PUNCT admet-144 121 1 7 7 NUM admet-144 121 2 , , PUNCT admet-144 121 3 panels panel NOUN admet-144 121 4 b b PROPN admet-144 121 5 and and CCONJ admet-144 121 6 c c PROPN admet-144 121 7 for for ADP admet-144 121 8 microsomes microsomes PROPN admet-144 121 9 ( ( PUNCT admet-144 121 10 afe afe NOUN admet-144 121 11 = = PROPN admet-144 121 12 0.76 0.76 NUM admet-144 121 13 , , PUNCT admet-144 121 14 gmfe gmfe NOUN admet-144 121 15 = = NOUN admet-144 121 16 2.11 2.11 NUM admet-144 121 17 ) ) PUNCT admet-144 121 18 ) ) PUNCT admet-144 121 19 and and CCONJ admet-144 121 20 hepatocytes hepatocytes PROPN admet-144 121 21 ( ( PUNCT admet-144 121 22 afe afe NOUN admet-144 121 23 = = PROPN admet-144 121 24 0.32 0.32 NUM admet-144 121 25 , , PUNCT admet-144 121 26 gmfe gmfe NOUN admet-144 121 27 = = NOUN admet-144 121 28 3.56 3.56 NUM admet-144 121 29 ) ) PUNCT admet-144 121 30 , , PUNCT admet-144 121 31 respectively respectively ADV admet-144 121 32 ) ) PUNCT admet-144 121 33 or or CCONJ admet-144 121 34 sinusoidal sinusoidal NOUN admet-144 121 35 uptake uptake ADJ admet-144 121 36 ( ( PUNCT admet-144 121 37 fig fig NOUN admet-144 121 38 . . PUNCT admet-144 122 1 7 7 NUM admet-144 122 2 , , PUNCT admet-144 122 3 panel panel NOUN admet-144 122 4 d d NOUN admet-144 122 5 , , PUNCT admet-144 122 6 afe afe PROPN admet-144 122 7 = = PROPN admet-144 122 8 1.71 1.71 NUM admet-144 122 9 , , PUNCT admet-144 122 10 gmfe gmfe NOUN admet-144 122 11 = = NOUN admet-144 122 12 1.84 1.84 NUM admet-144 122 13 ) ) PUNCT admet-144 122 14 data datum NOUN admet-144 122 15 . . PUNCT admet-144 123 1 figure figure NOUN admet-144 123 2 7 7 NUM admet-144 123 3 . . PUNCT admet-144 123 4 comparison comparison NOUN admet-144 123 5 of of ADP admet-144 123 6 the the DET admet-144 123 7 reported report VERB admet-144 123 8 ( ( PUNCT admet-144 123 9 clh clh NOUN admet-144 123 10 , , PUNCT admet-144 123 11 obs obs PROPN admet-144 123 12 ) ) PUNCT admet-144 123 13 and and CCONJ admet-144 123 14 predicted predict VERB admet-144 123 15 ( ( PUNCT admet-144 123 16 clh clh NOUN admet-144 123 17 , , PUNCT admet-144 123 18 pred pre VERB admet-144 123 19 ) ) PUNCT admet-144 123 20 hepatic hepatic ADJ admet-144 123 21 clearances clearance NOUN admet-144 123 22 using use VERB admet-144 123 23 different different ADJ admet-144 123 24 ivive ivive ADJ admet-144 123 25 methods method NOUN admet-144 123 26 . . PUNCT admet-144 124 1 panel panel NOUN admet-144 124 2 a a PRON admet-144 124 3 represents represent VERB admet-144 124 4 the the DET admet-144 124 5 relationship relationship NOUN admet-144 124 6 according accord VERB admet-144 124 7 to to ADP admet-144 124 8 the the DET admet-144 124 9 extended extended ADJ admet-144 124 10 clearance clearance NOUN admet-144 124 11 model model NOUN admet-144 124 12 ( ( PUNCT admet-144 124 13 ecm ecm PROPN admet-144 124 14 ) ) PUNCT admet-144 124 15 . . PUNCT admet-144 125 1 the the DET admet-144 125 2 panels panel NOUN admet-144 125 3 b b PROPN admet-144 125 4 and and CCONJ admet-144 125 5 c c PROPN admet-144 125 6 show show VERB admet-144 125 7 the the DET admet-144 125 8 predictions prediction NOUN admet-144 125 9 based base VERB admet-144 125 10 on on ADP admet-144 125 11 in in ADP admet-144 125 12 vitro vitro X admet-144 125 13 metabolism metabolism NOUN admet-144 125 14 data datum NOUN admet-144 125 15 from from ADP admet-144 125 16 human human ADJ admet-144 125 17 microsomes microsome NOUN admet-144 125 18 ( ( PUNCT admet-144 125 19 hlm hlm PROPN admet-144 125 20 ) ) PUNCT admet-144 125 21 and and CCONJ admet-144 125 22 hepatocytes hepatocyte NOUN admet-144 125 23 ( ( PUNCT admet-144 125 24 hh hh PROPN admet-144 125 25 ) ) PUNCT admet-144 125 26 , , PUNCT admet-144 125 27 respectively respectively ADV admet-144 125 28 , , PUNCT admet-144 125 29 whereas whereas SCONJ admet-144 125 30 panel panel NOUN admet-144 125 31 d d NOUN admet-144 125 32 is be AUX admet-144 125 33 the the DET admet-144 125 34 representation representation NOUN admet-144 125 35 based base VERB admet-144 125 36 on on ADP admet-144 125 37 sinusoidal sinusoidal NOUN admet-144 125 38 uptake uptake ADJ admet-144 125 39 data datum NOUN admet-144 125 40 from from ADP admet-144 125 41 suspended suspend VERB admet-144 125 42 human human ADJ admet-144 125 43 hepatocytes hepatocyte NOUN admet-144 125 44 ( ( PUNCT admet-144 125 45 shh shh NOUN admet-144 125 46 ) ) PUNCT admet-144 125 47 . . PUNCT admet-144 126 1 red red ADJ admet-144 126 2 diamonds diamond NOUN admet-144 126 3 , , PUNCT admet-144 126 4 green green ADJ admet-144 126 5 squares square NOUN admet-144 126 6 , , PUNCT admet-144 126 7 blue blue ADJ admet-144 126 8 triangles triangle NOUN admet-144 126 9 and and CCONJ admet-144 126 10 orange orange PROPN admet-144 126 11 circles circle NOUN admet-144 126 12 show show VERB admet-144 126 13 the the DET admet-144 126 14 class class NOUN admet-144 126 15 1 1 NUM admet-144 126 16 , , PUNCT admet-144 126 17 2 2 NUM admet-144 126 18 , , PUNCT admet-144 126 19 3 3 NUM admet-144 126 20 and and CCONJ admet-144 126 21 4 4 NUM admet-144 126 22 assignments assignment NOUN admet-144 126 23 according accord VERB admet-144 126 24 to to ADP admet-144 126 25 ecc ecc PROPN admet-144 126 26 ( ( PUNCT admet-144 126 27 table table NOUN admet-144 126 28 1 1 NUM admet-144 126 29 ) ) PUNCT admet-144 126 30 . . PUNCT admet-144 127 1 the the DET admet-144 127 2 blue blue ADJ admet-144 127 3 line line NOUN admet-144 127 4 represents represent VERB admet-144 127 5 the the DET admet-144 127 6 line line NOUN admet-144 127 7 of of ADP admet-144 127 8 unity unity NOUN admet-144 127 9 for for ADP admet-144 127 10 each each DET admet-144 127 11 panel panel NOUN admet-144 127 12 . . PUNCT admet-144 128 1 in in ADP admet-144 128 2 accordance accordance NOUN admet-144 128 3 with with ADP admet-144 128 4 previous previous ADJ admet-144 128 5 research research NOUN admet-144 128 6 , , PUNCT admet-144 128 7 the the DET admet-144 128 8 correlation correlation NOUN admet-144 128 9 analysis analysis NOUN admet-144 128 10 in in ADP admet-144 128 11 fig fig NOUN admet-144 128 12 . . PUNCT admet-144 129 1 7 7 NUM admet-144 129 2 reveals reveal VERB admet-144 129 3 a a DET admet-144 129 4 systematic systematic ADJ admet-144 129 5 underprediction underprediction NOUN admet-144 129 6 of of ADP admet-144 129 7 in in ADP admet-144 129 8 vivo vivo ADJ admet-144 129 9 hepatic hepatic ADJ admet-144 129 10 clearance clearance NOUN admet-144 129 11 when when SCONJ admet-144 129 12 using use VERB admet-144 129 13 metabolic metabolic NOUN admet-144 129 14 turn turn NOUN admet-144 129 15 - - PUNCT admet-144 129 16 over over ADP admet-144 129 17 data datum NOUN admet-144 129 18 from from ADP admet-144 129 19 human human ADJ admet-144 129 20 hepatocyte hepatocyte NOUN admet-144 129 21 incubations incubation NOUN admet-144 129 22 whereas whereas SCONJ admet-144 129 23 sinusoidal sinusoidal NOUN admet-144 129 24 uptake uptake ADJ admet-144 129 25 data datum NOUN admet-144 129 26 from from ADP admet-144 129 27 suspended suspend VERB admet-144 129 28 human human ADJ admet-144 129 29 hepatocytes hepatocyte NOUN admet-144 129 30 tend tend VERB admet-144 129 31 to to PART admet-144 129 32 over over ADV admet-144 129 33 - - PUNCT admet-144 129 34 predict predict VERB admet-144 129 35 the the DET admet-144 129 36 in in ADP admet-144 129 37 vivo vivo ADJ admet-144 129 38 situation situation NOUN admet-144 129 39 [ [ X admet-144 129 40 9,10 9,10 NUM admet-144 129 41 ] ] X admet-144 129 42 . . PUNCT admet-144 130 1 metabolic metabolic NOUN admet-144 130 2 clearance clearance NOUN admet-144 130 3 data datum NOUN admet-144 130 4 from from ADP admet-144 130 5 human human ADJ admet-144 130 6 liver liver NOUN admet-144 130 7 microsomes microsome NOUN admet-144 130 8 on on ADP admet-144 130 9 the the DET admet-144 130 10 other other ADJ admet-144 130 11 hand hand NOUN admet-144 130 12 are be AUX admet-144 130 13 highly highly ADV admet-144 130 14 scattered scatter VERB admet-144 130 15 along along ADP admet-144 130 16 the the DET admet-144 130 17 line line NOUN admet-144 130 18 of of ADP admet-144 130 19 unity unity NOUN admet-144 130 20 providing provide VERB admet-144 130 21 underand underand NOUN admet-144 130 22 over over ADP admet-144 130 23 - - PUNCT admet-144 130 24 estimations estimation NOUN admet-144 130 25 of of ADP admet-144 130 26 the the DET admet-144 130 27 observed observe VERB admet-144 130 28 human human ADJ admet-144 130 29 hepatic hepatic ADJ admet-144 130 30 clearance clearance NOUN admet-144 130 31 . . PUNCT admet-144 131 1 the the DET admet-144 131 2 potential potential ADJ admet-144 131 3 rate rate NOUN admet-144 131 4 - - PUNCT admet-144 131 5 determining determine VERB admet-144 131 6 role role NOUN admet-144 131 7 of of ADP admet-144 131 8 the the DET admet-144 131 9 hepatocyte hepatocyte NOUN admet-144 131 10 membrane membrane NOUN admet-144 131 11 ( ( PUNCT admet-144 131 12 missing miss VERB admet-144 131 13 in in ADP admet-144 131 14 the the DET admet-144 131 15 microsomal microsomal ADJ admet-144 131 16 system system NOUN admet-144 131 17 ) ) PUNCT admet-144 131 18 is be AUX admet-144 131 19 extensively extensively ADV admet-144 131 20 discussed discuss VERB admet-144 131 21 in in ADP admet-144 131 22 literature literature NOUN admet-144 131 23 . . PUNCT admet-144 132 1 in in ADP admet-144 132 2 line line NOUN admet-144 132 3 with with ADP admet-144 132 4 this this DET admet-144 132 5 theory theory NOUN admet-144 132 6 more more ADJ admet-144 132 7 in in ADP admet-144 132 8 - - PUNCT admet-144 132 9 depth depth NOUN admet-144 132 10 data datum NOUN admet-144 132 11 examination examination NOUN admet-144 132 12 reveals reveal VERB admet-144 132 13 that that SCONJ admet-144 132 14 metabolism metabolism NOUN admet-144 132 15 information information NOUN admet-144 132 16 from from ADP admet-144 132 17 microsomes microsome NOUN admet-144 132 18 and and CCONJ admet-144 132 19 hepatocytes hepatocyte NOUN admet-144 132 20 generally generally ADV admet-144 132 21 provide provide VERB admet-144 132 22 reasonable reasonable ADJ admet-144 132 23 results result NOUN admet-144 132 24 for for ADP admet-144 132 25 the the DET admet-144 132 26 ecc ecc PROPN admet-144 132 27 class class NOUN admet-144 132 28 1 1 NUM admet-144 132 29 and and CCONJ admet-144 132 30 2 2 NUM admet-144 132 31 compounds compound NOUN admet-144 132 32 while while SCONJ admet-144 132 33 hepatocyte hepatocyte NOUN admet-144 132 34 uptake uptake ADJ admet-144 132 35 data datum NOUN admet-144 132 36 seem seem VERB admet-144 132 37 to to PART admet-144 132 38 be be AUX admet-144 132 39 highly highly ADV admet-144 132 40 predictive predictive ADJ admet-144 132 41 for for ADP admet-144 132 42 the the DET admet-144 132 43 in in ADP admet-144 132 44 vivo vivo ADJ admet-144 132 45 hepatic hepatic ADJ admet-144 132 46 clearance clearance NOUN admet-144 132 47 of of ADP admet-144 132 48 ecc ecc PROPN admet-144 132 49 class class NOUN admet-144 132 50 3 3 NUM admet-144 132 51 compounds compound NOUN admet-144 132 52 . . PUNCT admet-144 133 1 ivive ivive PROPN admet-144 133 2 based base VERB admet-144 133 3 on on ADP admet-144 133 4 the the DET admet-144 133 5 extended extended ADJ admet-144 133 6 mechanistic mechanistic ADJ admet-144 133 7 model model NOUN admet-144 133 8 surely surely ADV admet-144 133 9 works work VERB admet-144 133 10 best well ADV admet-144 133 11 for for ADP admet-144 133 12 ecc ecc PROPN admet-144 133 13 class class NOUN admet-144 133 14 4 4 NUM admet-144 133 15 compounds compound NOUN admet-144 133 16 though though ADV admet-144 133 17 . . PUNCT admet-144 134 1 imposing impose VERB admet-144 134 2 these these DET admet-144 134 3 observations observation NOUN admet-144 134 4 on on ADP admet-144 134 5 admet admet PROPN admet-144 134 6 & & CCONJ admet-144 134 7 dmpk dmpk PROPN admet-144 134 8 3(1 3(1 NUM admet-144 134 9 ) ) PUNCT admet-144 134 10 ( ( PUNCT admet-144 134 11 2015 2015 NUM admet-144 134 12 ) ) PUNCT admet-144 134 13 1 1 NUM admet-144 134 14 - - SYM admet-144 134 15 14 14 NUM admet-144 134 16 extended extended ADJ admet-144 134 17 clearance clearance NOUN admet-144 134 18 concept concept NOUN admet-144 134 19 classification classification NOUN admet-144 134 20 system system NOUN admet-144 134 21 ( ( PUNCT admet-144 134 22 ecccs ecccs NOUN admet-144 134 23 ) ) PUNCT admet-144 134 24 doi doi NOUN admet-144 134 25 : : PUNCT admet-144 134 26 10.5599 10.5599 NUM admet-144 134 27 / / SYM admet-144 134 28 admet.3.1.144 admet.3.1.144 PROPN admet-144 134 29 9 9 NUM admet-144 134 30 the the DET admet-144 134 31 principles principle NOUN admet-144 134 32 of of ADP admet-144 134 33 ecc ecc PROPN admet-144 134 34 the the DET admet-144 134 35 expected expect VERB admet-144 134 36 performance performance NOUN admet-144 134 37 of of ADP admet-144 134 38 the the DET admet-144 134 39 different different ADJ admet-144 134 40 ivive ivive ADJ admet-144 134 41 approaches approach NOUN admet-144 134 42 can can AUX admet-144 134 43 be be AUX admet-144 134 44 summarized summarize VERB admet-144 134 45 as as SCONJ admet-144 134 46 depicted depict VERB admet-144 134 47 in in ADP admet-144 134 48 fig fig NOUN admet-144 134 49 . . PUNCT admet-144 135 1 8 8 X admet-144 135 2 . . PUNCT admet-144 136 1 it it PRON admet-144 136 2 is be AUX admet-144 136 3 self self NOUN admet-144 136 4 - - PUNCT admet-144 136 5 explanatory explanatory ADJ admet-144 136 6 that that SCONJ admet-144 136 7 with with ADP admet-144 136 8 increasing increase VERB admet-144 136 9 contribution contribution NOUN admet-144 136 10 of of ADP admet-144 136 11 renal renal ADJ admet-144 136 12 clearance clearance NOUN admet-144 136 13 the the DET admet-144 136 14 predictability predictability NOUN admet-144 136 15 of of ADP admet-144 136 16 all all DET admet-144 136 17 hepatobiliary hepatobiliary ADJ admet-144 136 18 ivive ivive ADJ admet-144 136 19 tools tool NOUN admet-144 136 20 for for ADP admet-144 136 21 overall overall ADJ admet-144 136 22 ( ( PUNCT admet-144 136 23 total total ADJ admet-144 136 24 ) ) PUNCT admet-144 136 25 clearance clearance NOUN admet-144 136 26 is be AUX admet-144 136 27 decreasing decrease VERB admet-144 136 28 ( ( PUNCT admet-144 136 29 tendency tendency NOUN admet-144 136 30 for for ADP admet-144 136 31 underestimation underestimation NOUN admet-144 136 32 ) ) PUNCT admet-144 136 33 . . PUNCT admet-144 137 1 based base VERB admet-144 137 2 on on ADP admet-144 137 3 above above ADP admet-144 137 4 discussion discussion NOUN admet-144 137 5 , , PUNCT admet-144 137 6 this this PRON admet-144 137 7 is be AUX admet-144 137 8 mainly mainly ADV admet-144 137 9 true true ADJ admet-144 137 10 for for ADP admet-144 137 11 ecc ecc PROPN admet-144 137 12 class class NOUN admet-144 137 13 3 3 NUM admet-144 137 14 and and CCONJ admet-144 137 15 4 4 NUM admet-144 137 16 compounds compound NOUN admet-144 137 17 while while SCONJ admet-144 137 18 the the DET admet-144 137 19 overall overall ADJ admet-144 137 20 prediction prediction NOUN admet-144 137 21 performance performance NOUN admet-144 137 22 for for ADP admet-144 137 23 ecc ecc PROPN admet-144 137 24 class class NOUN admet-144 137 25 1 1 NUM admet-144 137 26 and and CCONJ admet-144 137 27 2 2 NUM admet-144 137 28 compounds compound NOUN admet-144 137 29 likely likely ADV admet-144 137 30 remains remain VERB admet-144 137 31 good good ADJ admet-144 137 32 . . PUNCT admet-144 138 1 in in ADP admet-144 138 2 - - PUNCT admet-144 138 3 house house NOUN admet-144 138 4 research research NOUN admet-144 138 5 intending intend VERB admet-144 138 6 to to PART admet-144 138 7 improve improve VERB admet-144 138 8 bottom bottom ADJ admet-144 138 9 - - PUNCT admet-144 138 10 up up ADP admet-144 138 11 predictions prediction NOUN admet-144 138 12 for for ADP admet-144 138 13 overall overall ADJ admet-144 138 14 human human ADJ admet-144 138 15 clearance clearance NOUN admet-144 138 16 using use VERB admet-144 138 17 different different ADJ admet-144 138 18 in in ADP admet-144 138 19 vitro vitro X admet-144 138 20 and and CCONJ admet-144 138 21 in in ADP admet-144 138 22 vivo vivo ADJ admet-144 138 23 approaches approach NOUN admet-144 138 24 is be AUX admet-144 138 25 currently currently ADV admet-144 138 26 ongoing ongoing ADJ admet-144 138 27 . . PUNCT admet-144 139 1 figure figure NOUN admet-144 139 2 8 8 NUM admet-144 139 3 . . PUNCT admet-144 140 1 anticipated anticipate VERB admet-144 140 2 hepatobiliary hepatobiliary ADJ admet-144 140 3 ivive ivive ADJ admet-144 140 4 accuracy accuracy NOUN admet-144 140 5 of of ADP admet-144 140 6 different different ADJ admet-144 140 7 in in ADP admet-144 140 8 vitro vitro X admet-144 140 9 tools tool NOUN admet-144 140 10 : : PUNCT admet-144 140 11 metabolism metabolism NOUN admet-144 140 12 assessment assessment NOUN admet-144 140 13 in in ADP admet-144 140 14 human human ADJ admet-144 140 15 liver liver NOUN admet-144 140 16 microsomes microsome NOUN admet-144 140 17 ( ( PUNCT admet-144 140 18 hlm hlm PROPN admet-144 140 19 ) ) PUNCT admet-144 140 20 or or CCONJ admet-144 140 21 human human ADJ admet-144 140 22 hepatocytes hepatocyte NOUN admet-144 140 23 ( ( PUNCT admet-144 140 24 hh hh PROPN admet-144 140 25 ) ) PUNCT admet-144 140 26 , , PUNCT admet-144 140 27 uptake uptake ADJ admet-144 140 28 data datum NOUN admet-144 140 29 from from ADP admet-144 140 30 suspended suspend VERB admet-144 140 31 human human ADJ admet-144 140 32 hepatocytes hepatocyte NOUN admet-144 140 33 ( ( PUNCT admet-144 140 34 shh shh NOUN admet-144 140 35 ) ) PUNCT admet-144 140 36 and and CCONJ admet-144 140 37 integrated integrate VERB admet-144 140 38 approach approach NOUN admet-144 140 39 with with ADP admet-144 140 40 the the DET admet-144 140 41 extended extended ADJ admet-144 140 42 clearance clearance NOUN admet-144 140 43 model model NOUN admet-144 140 44 ( ( PUNCT admet-144 140 45 ecm ecm PROPN admet-144 140 46 ) ) PUNCT admet-144 140 47 . . PUNCT admet-144 141 1 for for ADP admet-144 141 2 the the DET admet-144 141 3 assignment assignment NOUN admet-144 141 4 the the DET admet-144 141 5 following follow VERB admet-144 141 6 assumptions assumption NOUN admet-144 141 7 were be AUX admet-144 141 8 made make VERB admet-144 141 9 : : PUNCT admet-144 141 10 ( ( PUNCT admet-144 141 11 i i NOUN admet-144 141 12 ) ) PUNCT admet-144 141 13 absence absence NOUN admet-144 141 14 of of ADP admet-144 141 15 significant significant ADJ admet-144 141 16 biliary biliary ADJ admet-144 141 17 secretion secretion NOUN admet-144 141 18 ( ( PUNCT admet-144 141 19 i.e. i.e. X admet-144 141 20 clint clint NOUN admet-144 141 21 , , PUNCT admet-144 141 22 sec sec PROPN admet-144 141 23 < < X admet-144 141 24 < < X admet-144 141 25 clint clint NOUN admet-144 141 26 , , PUNCT admet-144 141 27 met meet VERB admet-144 141 28 ) ) PUNCT admet-144 141 29 , , PUNCT admet-144 141 30 ( ( PUNCT admet-144 141 31 ii ii NOUN admet-144 141 32 ) ) PUNCT admet-144 141 33 absence absence NOUN admet-144 141 34 of of ADP admet-144 141 35 phase phase NOUN admet-144 141 36 ii ii NOUN admet-144 141 37 metabolism metabolism NOUN admet-144 141 38 and and CCONJ admet-144 141 39 , , PUNCT admet-144 141 40 ( ( PUNCT admet-144 141 41 iii iii NOUN admet-144 141 42 ) ) PUNCT admet-144 141 43 no no PRON admet-144 141 44 or or CCONJ admet-144 141 45 down down ADV admet-144 141 46 - - PUNCT admet-144 141 47 regulated regulate VERB admet-144 141 48 transporter transporter NOUN admet-144 141 49 activity activity NOUN admet-144 141 50 in in ADP admet-144 141 51 hh hh PROPN admet-144 141 52 . . PUNCT admet-144 142 1 static static ADJ admet-144 142 2 ddi ddi PROPN admet-144 142 3 predictions prediction NOUN admet-144 142 4 a a DET admet-144 142 5 perpetrator perpetrator NOUN admet-144 142 6 drug drug NOUN admet-144 142 7 may may AUX admet-144 142 8 inhibit inhibit VERB admet-144 142 9 any any DET admet-144 142 10 active active ADJ admet-144 142 11 clearance clearance NOUN admet-144 142 12 pathway pathway NOUN admet-144 142 13 contributing contribute VERB admet-144 142 14 to to ADP admet-144 142 15 the the DET admet-144 142 16 total total ADJ admet-144 142 17 hepatic hepatic ADJ admet-144 142 18 elimination elimination NOUN admet-144 142 19 of of ADP admet-144 142 20 a a DET admet-144 142 21 substrate substrate NOUN admet-144 142 22 . . PUNCT admet-144 143 1 accordingly accordingly ADV admet-144 143 2 , , PUNCT admet-144 143 3 based base VERB admet-144 143 4 on on ADP admet-144 143 5 eq eq ADP admet-144 143 6 . . PUNCT admet-144 144 1 ( ( PUNCT admet-144 144 2 1 1 NUM admet-144 144 3 ) ) PUNCT admet-144 144 4 ( ( PUNCT admet-144 144 5 assuming assume VERB admet-144 144 6 pseff pseff NOUN admet-144 144 7 , , PUNCT admet-144 144 8 act act NOUN admet-144 144 9 = = SYM admet-144 144 10 0 0 NUM admet-144 144 11 and and CCONJ admet-144 144 12 pseff pseff NOUN admet-144 144 13 , , PUNCT admet-144 144 14 pas pas NOUN admet-144 144 15 = = SYM admet-144 144 16 psinf psinf ADJ admet-144 144 17 , , PUNCT admet-144 144 18 pas pas PROPN admet-144 144 19 ) ) PUNCT admet-144 144 20 , , PUNCT admet-144 144 21 the the DET admet-144 144 22 overall overall ADJ admet-144 144 23 hepatic hepatic ADJ admet-144 144 24 intrinsic intrinsic ADJ admet-144 144 25 clearance clearance NOUN admet-144 144 26 in in ADP admet-144 144 27 the the DET admet-144 144 28 presence presence NOUN admet-144 144 29 of of ADP admet-144 144 30 a a DET admet-144 144 31 perpetrator perpetrator NOUN admet-144 144 32 ( ( PUNCT admet-144 144 33 clh clh NOUN admet-144 144 34 , , PUNCT admet-144 144 35 int int NOUN admet-144 144 36 , , PUNCT admet-144 144 37 i i PRON admet-144 144 38 ) ) PUNCT admet-144 144 39 can can AUX admet-144 144 40 be be AUX admet-144 144 41 expressed express VERB admet-144 144 42 as as SCONJ admet-144 144 43 follows follow VERB admet-144 144 44 [ [ X admet-144 144 45 1,7 1,7 NUM admet-144 144 46 ] ] NUM admet-144 144 47 : : PUNCT admet-144 144 48 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 144 49 , , PUNCT admet-144 144 50 𝑖𝑛𝑑 𝑖𝑛𝑑 PROPN admet-144 144 51 , , PUNCT admet-144 144 52 𝑖 𝑖 SYM admet-144 144 53 = = SYM admet-144 144 54 οΏ½ οΏ½ PROPN admet-144 144 55 1βˆ’ 1βˆ’ NUM admet-144 144 56 𝑓𝑖 𝑓𝑖 PROPN admet-144 144 57 , , PUNCT admet-144 144 58 𝑖𝑛𝑓 𝑖𝑛𝑓 NOUN admet-144 144 59 βˆ™ βˆ™ PROPN admet-144 144 60 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 144 61 , , PUNCT admet-144 144 62 π‘Žπ‘π‘‘ π‘Žπ‘π‘‘ PROPN admet-144 144 63 + + CCONJ admet-144 144 64 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 144 65 , , PUNCT admet-144 145 1 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 145 2 βˆ™ βˆ™ PROPN admet-144 145 3 [ [ PUNCT admet-144 145 4 1βˆ’ 1βˆ’ NUM admet-144 145 5 𝑓𝑖 𝑓𝑖 NOUN admet-144 145 6 , , PUNCT admet-144 145 7 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ ADP admet-144 145 8 βˆ™ βˆ™ PROPN admet-144 145 9 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 145 10 , , PUNCT admet-144 145 11 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ NOUN admet-144 145 12 + + CCONJ admet-144 145 13 ( ( PUNCT admet-144 145 14 1βˆ’ 1βˆ’ NUM admet-144 145 15 𝑓𝑖 𝑓𝑖 NOUN admet-144 145 16 , , PUNCT admet-144 145 17 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 145 18 ) ) PUNCT admet-144 145 19 βˆ™ βˆ™ PROPN admet-144 145 20 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 145 21 , , PUNCT admet-144 145 22 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 145 23 ] ] PUNCT admet-144 146 1 [ [ X admet-144 146 2 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 146 3 , , PUNCT admet-144 146 4 π‘π‘Žπ‘  π‘π‘Žπ‘  NOUN admet-144 146 5 + + CCONJ admet-144 146 6 ( ( PUNCT admet-144 146 7 1βˆ’ 1βˆ’ NUM admet-144 146 8 𝑓𝑖 𝑓𝑖 NOUN admet-144 146 9 , , PUNCT admet-144 146 10 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ ADJ admet-144 146 11 ) ) PUNCT admet-144 146 12 βˆ™ βˆ™ PROPN admet-144 146 13 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 146 14 , , PUNCT admet-144 146 15 π‘šπ‘’π‘‘ π‘šπ‘’π‘‘ PUNCT admet-144 146 16 + + NUM admet-144 146 17 1βˆ’ 1βˆ’ NUM admet-144 146 18 𝑓𝑖 𝑓𝑖 NOUN admet-144 146 19 , , PUNCT admet-144 146 20 𝑠𝑒𝑐 𝑠𝑒𝑐 ADJ admet-144 146 21 βˆ™ βˆ™ PROPN admet-144 146 22 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 146 23 , , PUNCT admet-144 146 24 𝑠𝑒𝑐 𝑠𝑒𝑐 NOUN admet-144 146 25 ] ] PUNCT admet-144 146 26 where where SCONJ admet-144 146 27 fi fi NOUN admet-144 146 28 , , PUNCT admet-144 146 29 inf inf NOUN admet-144 146 30 , , PUNCT admet-144 146 31 fi fi NOUN admet-144 146 32 , , PUNCT admet-144 146 33 sec sec PROPN admet-144 146 34 and and CCONJ admet-144 146 35 fi fi NOUN admet-144 146 36 , , PUNCT admet-144 146 37 met meet VERB admet-144 146 38 denote denote VERB admet-144 146 39 the the DET admet-144 146 40 inhibited inhibited ADJ admet-144 146 41 fractions fraction NOUN admet-144 146 42 of of ADP admet-144 146 43 active active ADJ admet-144 146 44 influx influx NOUN admet-144 146 45 , , PUNCT admet-144 146 46 canalicular canalicular ADJ admet-144 146 47 secretion secretion NOUN admet-144 146 48 , , PUNCT admet-144 146 49 and and CCONJ admet-144 146 50 metabolism metabolism NOUN admet-144 146 51 , , PUNCT admet-144 146 52 respectively respectively ADV admet-144 146 53 . . PUNCT admet-144 147 1 a a DET admet-144 147 2 fi fi NOUN admet-144 147 3 value value NOUN admet-144 147 4 of of ADP admet-144 147 5 zero zero NUM admet-144 147 6 thereby thereby ADV admet-144 147 7 indicates indicate VERB admet-144 147 8 no no DET admet-144 147 9 inhibition inhibition NOUN admet-144 147 10 whereas whereas SCONJ admet-144 147 11 a a DET admet-144 147 12 value value NOUN admet-144 147 13 of of ADP admet-144 147 14 one one NUM admet-144 147 15 refers refer VERB admet-144 147 16 to to ADP admet-144 147 17 ( ( PUNCT admet-144 147 18 3 3 X admet-144 147 19 ) ) PUNCT admet-144 147 20 camenisch camenisch PROPN admet-144 147 21 et et PROPN admet-144 147 22 al al PROPN admet-144 147 23 . . PROPN admet-144 147 24 admet admet PROPN admet-144 147 25 & & CCONJ admet-144 147 26 dmpk dmpk PROPN admet-144 147 27 3(1 3(1 NUM admet-144 147 28 ) ) PUNCT admet-144 147 29 ( ( PUNCT admet-144 147 30 2015 2015 NUM admet-144 147 31 ) ) PUNCT admet-144 147 32 1 1 NUM admet-144 147 33 - - SYM admet-144 147 34 14 14 NUM admet-144 147 35 10 10 NUM admet-144 147 36 complete complete ADJ admet-144 147 37 inhibition inhibition NOUN admet-144 147 38 . . PUNCT admet-144 148 1 based base VERB admet-144 148 2 on on ADP admet-144 148 3 this this DET admet-144 148 4 relationship relationship NOUN admet-144 148 5 the the DET admet-144 148 6 hepatic hepatic ADJ admet-144 148 7 clearance clearance NOUN admet-144 148 8 in in ADP admet-144 148 9 the the DET admet-144 148 10 presence presence NOUN admet-144 148 11 of of ADP admet-144 148 12 any any DET admet-144 148 13 perpetrator perpetrator NOUN admet-144 148 14 compound compound NOUN admet-144 148 15 ( ( PUNCT admet-144 148 16 clh clh NOUN admet-144 148 17 , , PUNCT admet-144 148 18 i i PROPN admet-144 148 19 ) ) PUNCT admet-144 148 20 can can AUX admet-144 148 21 be be AUX admet-144 148 22 anticipated anticipate VERB admet-144 148 23 in in ADP admet-144 148 24 accordance accordance NOUN admet-144 148 25 with with ADP admet-144 148 26 eq eq NOUN admet-144 148 27 . . PUNCT admet-144 149 1 ( ( PUNCT admet-144 149 2 2 2 NUM admet-144 149 3 ) ) PUNCT admet-144 149 4 . . PUNCT admet-144 150 1 following follow VERB admet-144 150 2 oral oral ADJ admet-144 150 3 ( ( PUNCT admet-144 150 4 po po NOUN admet-144 150 5 ) ) PUNCT admet-144 150 6 administration administration NOUN admet-144 150 7 of of ADP admet-144 150 8 a a DET admet-144 150 9 drug drug NOUN admet-144 150 10 and and CCONJ admet-144 150 11 its its PRON admet-144 150 12 perpetrator perpetrator NOUN admet-144 150 13 , , PUNCT admet-144 150 14 assuming assume VERB admet-144 150 15 the the DET admet-144 150 16 presence presence NOUN admet-144 150 17 of of ADP admet-144 150 18 hepatic hepatic NOUN admet-144 150 19 and and CCONJ admet-144 150 20 a a DET admet-144 150 21 non non ADJ admet-144 150 22 - - ADJ admet-144 150 23 hepatic hepatic ADJ admet-144 150 24 ( ( PUNCT admet-144 150 25 e.g. e.g. ADV admet-144 150 26 renal renal ADJ admet-144 150 27 ) ) PUNCT admet-144 150 28 elimination elimination NOUN admet-144 150 29 pathways pathway NOUN admet-144 150 30 and and CCONJ admet-144 150 31 that that SCONJ admet-144 150 32 the the DET admet-144 150 33 perpetrator perpetrator NOUN admet-144 150 34 drug drug NOUN admet-144 150 35 only only ADV admet-144 150 36 affects affect VERB admet-144 150 37 active active ADJ admet-144 150 38 processes process NOUN admet-144 150 39 in in ADP admet-144 150 40 the the DET admet-144 150 41 liver liver NOUN admet-144 150 42 , , PUNCT admet-144 150 43 the the DET admet-144 150 44 exposure exposure NOUN admet-144 150 45 ( ( PUNCT admet-144 150 46 auc auc NOUN admet-144 150 47 ) ) PUNCT admet-144 150 48 fold fold NOUN admet-144 150 49 - - PUNCT admet-144 150 50 change change NOUN admet-144 150 51 ( ( PUNCT admet-144 150 52 expressed express VERB admet-144 150 53 as as ADP admet-144 150 54 aucpo aucpo NOUN admet-144 150 55 , , PUNCT admet-144 150 56 i i PROPN admet-144 150 57 / / SYM admet-144 150 58 aucpo aucpo NOUN admet-144 150 59 ) ) PUNCT admet-144 150 60 can can AUX admet-144 150 61 be be AUX admet-144 150 62 described describe VERB admet-144 150 63 as as ADP admet-144 150 64 follows follow VERB admet-144 150 65 : : PUNCT admet-144 150 66 π΄π‘ˆπΆπ‘π‘œ π΄π‘ˆπΆπ‘π‘œ VERB admet-144 150 67 , , PUNCT admet-144 150 68 𝑖 𝑖 NOUN admet-144 150 69 π΄π‘ˆπΆπ‘π‘œ π΄π‘ˆπΆπ‘π‘œ NOUN admet-144 151 1 = = PUNCT admet-144 151 2 πΉβ„Ž πΉβ„Ž PROPN admet-144 151 3 , , PUNCT admet-144 151 4 𝑖 𝑖 SYM admet-144 152 1 πΉβ„Ž πΉβ„Ž PROPN admet-144 152 2 βˆ™ βˆ™ PROPN admet-144 152 3 1 1 NUM admet-144 152 4 π‘“π‘›β„Ž π‘“π‘›β„Ž NOUN admet-144 152 5 βˆ™ βˆ™ PROPN admet-144 152 6 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 152 7 , , PUNCT admet-144 152 8 𝑖 𝑖 SYM admet-144 152 9 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 152 10 οΏ½ οΏ½ PROPN admet-144 152 11 + + CCONJ admet-144 152 12 1βˆ’ 1βˆ’ NUM admet-144 152 13 π‘“π‘›β„Ž π‘“π‘›β„Ž NOUN admet-144 152 14 where where SCONJ admet-144 152 15 , , PUNCT admet-144 152 16 fh fh PROPN admet-144 152 17 (= (= NUM admet-144 152 18 1 1 NUM admet-144 152 19 - - PUNCT admet-144 152 20 clh clh NOUN admet-144 152 21 / / SYM admet-144 152 22 qh qh NOUN admet-144 152 23 ) ) PUNCT admet-144 152 24 and and CCONJ admet-144 152 25 fh fh PROPN admet-144 152 26 , , PUNCT admet-144 152 27 i i PRON admet-144 152 28 (= (= VERB admet-144 152 29 1 1 X admet-144 152 30 - - PUNCT admet-144 152 31 clh clh NOUN admet-144 152 32 , , PUNCT admet-144 152 33 i i PROPN admet-144 152 34 / / SYM admet-144 152 35 qh qh NOUN admet-144 152 36 ) ) PUNCT admet-144 152 37 are be AUX admet-144 152 38 the the DET admet-144 152 39 fractions fraction NOUN admet-144 152 40 of of ADP admet-144 152 41 the the DET admet-144 152 42 oral oral ADJ admet-144 152 43 dose dose NOUN admet-144 152 44 escaping escape VERB admet-144 152 45 hepatic hepatic ADJ admet-144 152 46 first first ADJ admet-144 152 47 - - PUNCT admet-144 152 48 pass pass NOUN admet-144 152 49 in in ADP admet-144 152 50 the the DET admet-144 152 51 absence absence NOUN admet-144 152 52 and and CCONJ admet-144 152 53 presence presence NOUN admet-144 152 54 of of ADP admet-144 152 55 a a DET admet-144 152 56 perpetrator perpetrator NOUN admet-144 152 57 , , PUNCT admet-144 152 58 respectively respectively ADV admet-144 152 59 . . PUNCT admet-144 153 1 under under ADP admet-144 153 2 the the DET admet-144 153 3 additional additional ADJ admet-144 153 4 assumption assumption NOUN admet-144 153 5 that that SCONJ admet-144 153 6 the the DET admet-144 153 7 liver liver NOUN admet-144 153 8 is be AUX admet-144 153 9 the the DET admet-144 153 10 only only ADJ admet-144 153 11 clearance clearance NOUN admet-144 153 12 organ organ NOUN admet-144 153 13 ( ( PUNCT admet-144 153 14 i.e. i.e. X admet-144 153 15 fnh fnh X admet-144 153 16 = = SYM admet-144 153 17 1 1 NUM admet-144 153 18 ) ) PUNCT admet-144 153 19 eq eq NOUN admet-144 153 20 . . PUNCT admet-144 153 21 ( ( PUNCT admet-144 153 22 4 4 X admet-144 153 23 ) ) PUNCT admet-144 153 24 simplifies simplifie NOUN admet-144 153 25 to to PART admet-144 153 26 : : PUNCT admet-144 153 27 π΄π‘ˆπΆπ‘π‘œ π΄π‘ˆπΆπ‘π‘œ VERB admet-144 153 28 , , PUNCT admet-144 153 29 𝑖 𝑖 NOUN admet-144 153 30 π΄π‘ˆπΆπ‘π‘œ π΄π‘ˆπΆπ‘π‘œ NOUN admet-144 153 31 = = NOUN admet-144 153 32 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 153 33 , , PUNCT admet-144 153 34 𝑖𝑛𝑑 𝑖𝑛𝑑 NOUN admet-144 153 35 πΆπΏβ„Ž πΆπΏβ„Ž NOUN admet-144 153 36 , , PUNCT admet-144 153 37 𝑖𝑛𝑑 𝑖𝑛𝑑 PROPN admet-144 153 38 , , PUNCT admet-144 153 39 𝑖 𝑖 NOUN admet-144 153 40 in in ADP admet-144 153 41 an an DET admet-144 153 42 abbreviated abbreviate VERB admet-144 153 43 manner manner NOUN admet-144 153 44 , , PUNCT admet-144 153 45 based base VERB admet-144 153 46 on on ADP admet-144 153 47 eq eq ADP admet-144 153 48 . . PROPN admet-144 153 49 5 5 NUM admet-144 153 50 and and CCONJ admet-144 153 51 previous previous ADJ admet-144 153 52 discussion discussion NOUN admet-144 153 53 , , PUNCT admet-144 153 54 the the DET admet-144 153 55 drug drug NOUN admet-144 153 56 - - PUNCT admet-144 153 57 drug drug NOUN admet-144 153 58 interaction interaction NOUN admet-144 153 59 ( ( PUNCT admet-144 153 60 ddi ddi ADJ admet-144 153 61 ) ) PUNCT admet-144 153 62 potential potential NOUN admet-144 153 63 for for ADP admet-144 153 64 the the DET admet-144 153 65 four four NUM admet-144 153 66 ecm ecm NOUN admet-144 153 67 cases case NOUN admet-144 153 68 in in ADP admet-144 153 69 fig fig NOUN admet-144 153 70 . . PUNCT admet-144 154 1 1 1 NUM admet-144 154 2 can can AUX admet-144 154 3 therefore therefore ADV admet-144 154 4 be be AUX admet-144 154 5 represented represent VERB admet-144 154 6 as as SCONJ admet-144 154 7 shown show VERB admet-144 154 8 in in ADP admet-144 154 9 fig fig NOUN admet-144 154 10 . . PUNCT admet-144 155 1 9 9 X admet-144 155 2 . . X admet-144 155 3 figure figure NOUN admet-144 155 4 9 9 NUM admet-144 155 5 . . PUNCT admet-144 155 6 compound compound NOUN admet-144 155 7 class class NOUN admet-144 155 8 - - PUNCT admet-144 155 9 dependent dependent ADJ admet-144 155 10 ddi ddi NOUN admet-144 155 11 prediction prediction NOUN admet-144 155 12 ( ( PUNCT admet-144 155 13 inner inner ADJ admet-144 155 14 panel panel NOUN admet-144 155 15 ) ) PUNCT admet-144 155 16 according accord VERB admet-144 155 17 to to ADP admet-144 155 18 eq eq PROPN admet-144 155 19 . . PROPN admet-144 155 20 5 5 NUM admet-144 155 21 for for ADP admet-144 155 22 the the DET admet-144 155 23 four four NUM admet-144 155 24 different different ADJ admet-144 155 25 ecm ecm NOUN admet-144 155 26 cases case NOUN admet-144 155 27 based base VERB admet-144 155 28 on on ADP admet-144 155 29 different different ADJ admet-144 155 30 pre pre NOUN admet-144 155 31 - - NOUN admet-144 155 32 requisites requisite NOUN admet-144 155 33 ( ( PUNCT admet-144 155 34 outer outer ADJ admet-144 155 35 panel panel NOUN admet-144 155 36 ) ) PUNCT admet-144 155 37 . . PUNCT admet-144 156 1 i i PRON admet-144 156 2 refers refer VERB admet-144 156 3 to to ADP admet-144 156 4 a a DET admet-144 156 5 change change NOUN admet-144 156 6 in in ADP admet-144 156 7 clearance clearance NOUN admet-144 156 8 in in ADP admet-144 156 9 the the DET admet-144 156 10 presence presence NOUN admet-144 156 11 of of ADP admet-144 156 12 any any DET admet-144 156 13 perpetrator perpetrator NOUN admet-144 156 14 compound compound NOUN admet-144 156 15 . . PUNCT admet-144 157 1 fig fig NOUN admet-144 157 2 . . PUNCT admet-144 158 1 10 10 NUM admet-144 158 2 depicts depict VERB admet-144 158 3 the the DET admet-144 158 4 predicted predict VERB admet-144 158 5 static static ADJ admet-144 158 6 ddi ddi PROPN admet-144 158 7 risk risk NOUN admet-144 158 8 assessment assessment NOUN admet-144 158 9 of of ADP admet-144 158 10 3 3 NUM admet-144 158 11 representative representative ADJ admet-144 158 12 compounds compound NOUN admet-144 158 13 from from ADP admet-144 158 14 our our PRON admet-144 158 15 dataset dataset NOUN admet-144 158 16 ( ( PUNCT admet-144 158 17 namely namely ADV admet-144 158 18 the the DET admet-144 158 19 ecm ecm PROPN admet-144 158 20 class class NOUN admet-144 158 21 2 2 NUM admet-144 158 22 compound compound NOUN admet-144 158 23 verapamil verapamil NOUN admet-144 158 24 , , PUNCT admet-144 158 25 digoxin digoxin NOUN admet-144 158 26 as as ADP admet-144 158 27 a a DET admet-144 158 28 typical typical ADJ admet-144 158 29 ecm ecm NOUN admet-144 158 30 class class NOUN admet-144 158 31 3 3 NUM admet-144 158 32 compound compound NOUN admet-144 158 33 and and CCONJ admet-144 158 34 pravastatin pravastatin NOUN admet-144 158 35 representing represent VERB admet-144 158 36 the the DET admet-144 158 37 ecm ecm NOUN admet-144 158 38 class class NOUN admet-144 158 39 4 4 NUM admet-144 158 40 ) ) PUNCT admet-144 158 41 according accord VERB admet-144 158 42 to to ADP admet-144 158 43 eq eq PROPN admet-144 158 44 . . PUNCT admet-144 159 1 ( ( PUNCT admet-144 159 2 4 4 NUM admet-144 159 3 ) ) PUNCT admet-144 159 4 and and CCONJ admet-144 159 5 eq eq NOUN admet-144 159 6 . . PUNCT admet-144 160 1 ( ( PUNCT admet-144 160 2 5 5 NUM admet-144 160 3 ) ) PUNCT admet-144 160 4 , , PUNCT admet-144 160 5 assuming assume VERB admet-144 160 6 90 90 NUM admet-144 160 7 % % NOUN admet-144 160 8 inhibition inhibition NOUN admet-144 160 9 of of ADP admet-144 160 10 the the DET admet-144 160 11 respective respective ADJ admet-144 160 12 ( ( PUNCT admet-144 160 13 4 4 NUM admet-144 160 14 ) ) PUNCT admet-144 160 15 ( ( PUNCT admet-144 160 16 5 5 X admet-144 160 17 ) ) PUNCT admet-144 160 18 admet admet PROPN admet-144 160 19 & & CCONJ admet-144 160 20 dmpk dmpk PROPN admet-144 160 21 3(1 3(1 NUM admet-144 160 22 ) ) PUNCT admet-144 160 23 ( ( PUNCT admet-144 160 24 2015 2015 NUM admet-144 160 25 ) ) PUNCT admet-144 160 26 1 1 NUM admet-144 160 27 - - SYM admet-144 160 28 14 14 NUM admet-144 160 29 extended extended ADJ admet-144 160 30 clearance clearance NOUN admet-144 160 31 concept concept NOUN admet-144 160 32 classification classification NOUN admet-144 160 33 system system NOUN admet-144 160 34 ( ( PUNCT admet-144 160 35 ecccs ecccs NOUN admet-144 160 36 ) ) PUNCT admet-144 160 37 doi doi NOUN admet-144 160 38 : : PUNCT admet-144 160 39 10.5599 10.5599 NUM admet-144 160 40 / / SYM admet-144 160 41 admet.3.1.144 admet.3.1.144 PROPN admet-144 160 42 11 11 NUM admet-144 160 43 processes process NOUN admet-144 160 44 ( ( PUNCT admet-144 160 45 i.e. i.e. X admet-144 160 46 fi fi NOUN admet-144 160 47 , , PUNCT admet-144 160 48 inf inf NOUN admet-144 160 49 = = SYM admet-144 160 50 fi fi NOUN admet-144 160 51 , , PUNCT admet-144 160 52 met meet VERB admet-144 160 53 = = SYM admet-144 160 54 fi fi NOUN admet-144 160 55 , , PUNCT admet-144 160 56 sec sec PROPN admet-144 160 57 = = NUM admet-144 160 58 0.9 0.9 NUM admet-144 160 59 , , PUNCT admet-144 160 60 not not PART admet-144 160 61 taking take VERB admet-144 160 62 into into ADP admet-144 160 63 consideration consideration NOUN admet-144 160 64 fractional fractional ADJ admet-144 160 65 contributions contribution NOUN admet-144 160 66 of of ADP admet-144 160 67 different different ADJ admet-144 160 68 enzymes enzyme NOUN admet-144 160 69 or or CCONJ admet-144 160 70 transporters transporter NOUN admet-144 160 71 to to ADP admet-144 160 72 overall overall ADJ admet-144 160 73 metabolic metabolic NOUN admet-144 160 74 or or CCONJ admet-144 160 75 transport transport NOUN admet-144 160 76 clearance clearance NOUN admet-144 160 77 ) ) PUNCT admet-144 160 78 . . PUNCT admet-144 161 1 in in ADP admet-144 161 2 the the DET admet-144 161 3 absence absence NOUN admet-144 161 4 of of ADP admet-144 161 5 a a DET admet-144 161 6 renal renal ADJ admet-144 161 7 clearance clearance NOUN admet-144 161 8 contribution contribution NOUN admet-144 161 9 ( ( PUNCT admet-144 161 10 fig fig NOUN admet-144 161 11 . . PUNCT admet-144 161 12 10 10 NUM admet-144 161 13 , , PUNCT admet-144 161 14 panel panel NOUN admet-144 161 15 a a PRON admet-144 161 16 ) ) PUNCT admet-144 161 17 , , PUNCT admet-144 161 18 in in ADP admet-144 161 19 accordance accordance NOUN admet-144 161 20 with with ADP admet-144 161 21 the the DET admet-144 161 22 extended extended ADJ admet-144 161 23 clearance clearance NOUN admet-144 161 24 model model NOUN admet-144 161 25 , , PUNCT admet-144 161 26 for for ADP admet-144 161 27 the the DET admet-144 161 28 ecm ecm PROPN admet-144 161 29 class class NOUN admet-144 161 30 2 2 NUM admet-144 161 31 compound compound NOUN admet-144 161 32 in in ADP admet-144 161 33 our our PRON admet-144 161 34 selection selection NOUN admet-144 161 35 , , PUNCT admet-144 161 36 metabolism metabolism NOUN admet-144 161 37 is be AUX admet-144 161 38 identified identify VERB admet-144 161 39 as as ADP admet-144 161 40 the the DET admet-144 161 41 major major ADJ admet-144 161 42 clearance clearance NOUN admet-144 161 43 mechanism mechanism NOUN admet-144 161 44 primarily primarily ADV admet-144 161 45 responsible responsible ADJ admet-144 161 46 for for ADP admet-144 161 47 causing cause VERB admet-144 161 48 ddi ddi PROPN admet-144 161 49 ’s ’s PART admet-144 161 50 . . PUNCT admet-144 162 1 selective selective ADJ admet-144 162 2 inhibition inhibition NOUN admet-144 162 3 of of ADP admet-144 162 4 active active ADJ admet-144 162 5 hepatic hepatic ADJ admet-144 162 6 influx influx NOUN admet-144 162 7 or or CCONJ admet-144 162 8 biliary biliary NOUN admet-144 162 9 secretion secretion NOUN admet-144 162 10 has have VERB admet-144 162 11 no no DET admet-144 162 12 significant significant ADJ admet-144 162 13 effect effect NOUN admet-144 162 14 on on ADP admet-144 162 15 exposure exposure NOUN admet-144 162 16 though though ADV admet-144 162 17 . . PUNCT admet-144 163 1 a a DET admet-144 163 2 similarly similarly ADV admet-144 163 3 distinct distinct ADJ admet-144 163 4 overall overall ADJ admet-144 163 5 ddi ddi ADJ admet-144 163 6 behavior behavior NOUN admet-144 163 7 can can AUX admet-144 163 8 be be AUX admet-144 163 9 derived derive VERB admet-144 163 10 for for ADP admet-144 163 11 the the DET admet-144 163 12 ecm ecm PROPN admet-144 163 13 class class NOUN admet-144 163 14 3 3 NUM admet-144 163 15 compound compound NOUN admet-144 163 16 digoxin digoxin NOUN admet-144 163 17 with with ADP admet-144 163 18 sinusoidal sinusoidal ADJ admet-144 163 19 transporter transporter NOUN admet-144 163 20 inhibition inhibition NOUN admet-144 163 21 being be AUX admet-144 163 22 the the DET admet-144 163 23 major major ADJ admet-144 163 24 mechanism mechanism NOUN admet-144 163 25 causing cause VERB admet-144 163 26 the the DET admet-144 163 27 interaction interaction NOUN admet-144 163 28 . . PUNCT admet-144 164 1 for for ADP admet-144 164 2 the the DET admet-144 164 3 ecm ecm PROPN admet-144 164 4 class class NOUN admet-144 164 5 4 4 NUM admet-144 164 6 compound compound NOUN admet-144 164 7 pravastatin pravastatin NOUN admet-144 164 8 , , PUNCT admet-144 164 9 assuming assume VERB admet-144 164 10 absence absence NOUN admet-144 164 11 of of ADP admet-144 164 12 a a DET admet-144 164 13 renal renal ADJ admet-144 164 14 clearance clearance NOUN admet-144 164 15 contribution contribution NOUN admet-144 164 16 , , PUNCT admet-144 164 17 we we PRON admet-144 164 18 predict predict VERB admet-144 164 19 a a DET admet-144 164 20 substantial substantial ADJ admet-144 164 21 auc auc NOUN admet-144 164 22 change change NOUN admet-144 164 23 upon upon SCONJ admet-144 164 24 concomitant concomitant ADJ admet-144 164 25 inhibition inhibition NOUN admet-144 164 26 of of ADP admet-144 164 27 hepatic hepatic ADJ admet-144 164 28 uptake uptake NOUN admet-144 164 29 , , PUNCT admet-144 164 30 biliary biliary ADJ admet-144 164 31 secretion secretion NOUN admet-144 164 32 and and CCONJ admet-144 164 33 metabolism metabolism NOUN admet-144 164 34 whereas whereas SCONJ admet-144 164 35 inhibition inhibition NOUN admet-144 164 36 of of ADP admet-144 164 37 the the DET admet-144 164 38 single single ADJ admet-144 164 39 clearance clearance NOUN admet-144 164 40 pathways pathway NOUN admet-144 164 41 results result VERB admet-144 164 42 in in ADP admet-144 164 43 comparatively comparatively ADV admet-144 164 44 moderate moderate ADJ admet-144 164 45 auc auc NOUN admet-144 164 46 ratios ratio NOUN admet-144 164 47 . . PUNCT admet-144 165 1 taking take VERB admet-144 165 2 the the DET admet-144 165 3 clinically clinically ADV admet-144 165 4 observed observe VERB admet-144 165 5 fnh fnh PROPN admet-144 165 6 values value NOUN admet-144 165 7 according accord VERB admet-144 165 8 to to ADP admet-144 165 9 eq eq PROPN admet-144 165 10 . . PUNCT admet-144 166 1 ( ( PUNCT admet-144 166 2 4 4 NUM admet-144 166 3 ) ) PUNCT admet-144 166 4 into into ADP admet-144 166 5 account account NOUN admet-144 166 6 , , PUNCT admet-144 166 7 the the DET admet-144 166 8 individual individual NOUN admet-144 166 9 as as ADV admet-144 166 10 well well ADV admet-144 166 11 as as ADP admet-144 166 12 the the DET admet-144 166 13 overall overall ADJ admet-144 166 14 ddi ddi ADJ admet-144 166 15 risk risk NOUN admet-144 166 16 assessment assessment NOUN admet-144 166 17 of of ADP admet-144 166 18 verapamil verapamil NOUN admet-144 166 19 is be AUX admet-144 166 20 only only ADV admet-144 166 21 marginally marginally ADV admet-144 166 22 effected effect VERB admet-144 166 23 whereas whereas SCONJ admet-144 166 24 the the DET admet-144 166 25 impact impact NOUN admet-144 166 26 on on ADP admet-144 166 27 the the DET admet-144 166 28 projected project VERB admet-144 166 29 exposure exposure NOUN admet-144 166 30 changes change NOUN admet-144 166 31 for for ADP admet-144 166 32 digoxin digoxin NOUN admet-144 166 33 and and CCONJ admet-144 166 34 pravastatin pravastatin NOUN admet-144 166 35 is be AUX admet-144 166 36 significant significant ADJ admet-144 166 37 ( ( PUNCT admet-144 166 38 e.g. e.g. ADV admet-144 166 39 the the DET admet-144 166 40 overall overall ADJ admet-144 166 41 aucpo aucpo NOUN admet-144 166 42 , , PUNCT admet-144 166 43 i i PROPN admet-144 166 44 / / SYM admet-144 167 1 aucpo aucpo NOUN admet-144 167 2 ratio ratio NOUN admet-144 167 3 for for ADP admet-144 167 4 pravastatin pravastatin NOUN admet-144 167 5 decreases decrease VERB admet-144 167 6 about about ADV admet-144 167 7 8 8 NUM admet-144 167 8 - - NOUN admet-144 167 9 fold fold ADJ admet-144 167 10 ) ) PUNCT admet-144 167 11 ( ( PUNCT admet-144 167 12 fig fig NOUN admet-144 167 13 . . PUNCT admet-144 168 1 10 10 NUM admet-144 168 2 , , PUNCT admet-144 168 3 panel panel NOUN admet-144 168 4 b b NOUN admet-144 168 5 ) ) PUNCT admet-144 168 6 . . PUNCT admet-144 169 1 this this DET admet-144 169 2 concept concept NOUN admet-144 169 3 is be AUX admet-144 169 4 well well ADV admet-144 169 5 reflected reflect VERB admet-144 169 6 by by ADP admet-144 169 7 ecm ecm NOUN admet-144 169 8 and and CCONJ admet-144 169 9 can can AUX admet-144 169 10 be be AUX admet-144 169 11 rationalized rationalize VERB admet-144 169 12 by by ADP admet-144 169 13 the the DET admet-144 169 14 process process NOUN admet-144 169 15 inter inter NOUN admet-144 169 16 - - NOUN admet-144 169 17 dependencies dependency NOUN admet-144 169 18 as as SCONJ admet-144 169 19 discussed discuss VERB admet-144 169 20 above above ADV admet-144 169 21 . . PUNCT admet-144 170 1 it it PRON admet-144 170 2 is be AUX admet-144 170 3 noteworthy noteworthy ADJ admet-144 170 4 to to PART admet-144 170 5 mention mention VERB admet-144 170 6 at at ADP admet-144 170 7 this this DET admet-144 170 8 point point NOUN admet-144 170 9 , , PUNCT admet-144 170 10 that that SCONJ admet-144 170 11 the the DET admet-144 170 12 extended extended ADJ admet-144 170 13 clearance clearance NOUN admet-144 170 14 model model NOUN admet-144 170 15 represents represent VERB admet-144 170 16 the the DET admet-144 170 17 four four NUM admet-144 170 18 extremes extreme NOUN admet-144 170 19 of of ADP admet-144 170 20 hepatobiliary hepatobiliary ADJ admet-144 170 21 elimination elimination NOUN admet-144 170 22 and and CCONJ admet-144 170 23 that that SCONJ admet-144 170 24 most most ADJ admet-144 170 25 drugs drug NOUN admet-144 170 26 settle settle VERB admet-144 170 27 somewhere somewhere ADV admet-144 170 28 in in ADP admet-144 170 29 - - PUNCT admet-144 170 30 between between ADP admet-144 170 31 the the DET admet-144 170 32 ultimate ultimate ADJ admet-144 170 33 limits limit NOUN admet-144 170 34 given give VERB admet-144 170 35 in in ADP admet-144 170 36 fig fig NOUN admet-144 170 37 . . PUNCT admet-144 171 1 1 1 X admet-144 171 2 . . X admet-144 171 3 to to PART admet-144 171 4 eventually eventually ADV admet-144 171 5 predict predict VERB admet-144 171 6 the the DET admet-144 171 7 overall overall ADJ admet-144 171 8 ddi ddi ADJ admet-144 171 9 potential potential NOUN admet-144 171 10 of of ADP admet-144 171 11 drug drug NOUN admet-144 171 12 molecules molecule NOUN admet-144 171 13 it it PRON admet-144 171 14 is be AUX admet-144 171 15 therefore therefore ADV admet-144 171 16 essential essential ADJ admet-144 171 17 to to AUX admet-144 171 18 ( ( PUNCT admet-144 171 19 quantitatively quantitatively ADV admet-144 171 20 ) ) PUNCT admet-144 171 21 assess assess VERB admet-144 171 22 all all DET admet-144 171 23 the the DET admet-144 171 24 individual individual ADJ admet-144 171 25 hepatic hepatic ADJ admet-144 171 26 process process NOUN admet-144 171 27 contributions contribution NOUN admet-144 171 28 as as SCONJ admet-144 171 29 defined define VERB admet-144 171 30 by by ADP admet-144 171 31 eq eq PROPN admet-144 171 32 . . PUNCT admet-144 172 1 ( ( PUNCT admet-144 172 2 1 1 NUM admet-144 172 3 ) ) PUNCT admet-144 172 4 . . PUNCT admet-144 173 1 figure figure NOUN admet-144 173 2 10 10 NUM admet-144 173 3 . . PUNCT admet-144 174 1 static static ADJ admet-144 174 2 victim victim NOUN admet-144 174 3 drug drug NOUN admet-144 174 4 ddi ddi NOUN admet-144 174 5 predictions prediction NOUN admet-144 174 6 for for ADP admet-144 174 7 verapamil verapamil NOUN admet-144 174 8 ( ( PUNCT admet-144 174 9 cyp2c8 cyp2c8 ADV admet-144 174 10 , , PUNCT admet-144 174 11 cyp3a cyp3a NOUN admet-144 174 12 and and CCONJ admet-144 174 13 p p NOUN admet-144 174 14 - - PUNCT admet-144 174 15 gp gp NOUN admet-144 174 16 ) ) PUNCT admet-144 174 17 , , PUNCT admet-144 174 18 digoxin digoxin NOUN admet-144 174 19 ( ( PUNCT admet-144 174 20 p p NOUN admet-144 174 21 - - PUNCT admet-144 174 22 gp gp NOUN admet-144 174 23 , , PUNCT admet-144 174 24 cyp3a cyp3a NOUN admet-144 174 25 and and CCONJ admet-144 174 26 unknown unknown ADJ admet-144 174 27 sodium sodium NOUN admet-144 174 28 - - PUNCT admet-144 174 29 dependent dependent ADJ admet-144 174 30 sinusoidal sinusoidal NOUN admet-144 174 31 uptake uptake ADJ admet-144 174 32 transporter transporter NOUN admet-144 174 33 ) ) PUNCT admet-144 174 34 and and CCONJ admet-144 174 35 pravastatin pravastatin NOUN admet-144 174 36 ( ( PUNCT admet-144 174 37 bcrp bcrp ADV admet-144 174 38 , , PUNCT admet-144 174 39 mrp2 mrp2 PROPN admet-144 174 40 , , PUNCT admet-144 174 41 oatp1b1 oatp1b1 NUM admet-144 174 42 , , PUNCT admet-144 174 43 oatp1b3 oatp1b3 PROPN admet-144 174 44 , , PUNCT admet-144 174 45 oatp2b1 oatp2b1 NUM admet-144 174 46 and and CCONJ admet-144 174 47 cyp3a4 cyp3a4 PROPN admet-144 174 48 ) ) PUNCT admet-144 174 49 according accord VERB admet-144 174 50 to to ADP admet-144 174 51 eq eq PROPN admet-144 174 52 . . PUNCT admet-144 175 1 ( ( PUNCT admet-144 175 2 5 5 NUM admet-144 175 3 ) ) PUNCT admet-144 175 4 ( ( PUNCT admet-144 175 5 panel panel NOUN admet-144 175 6 a a NOUN admet-144 175 7 ) ) PUNCT admet-144 175 8 and and CCONJ admet-144 175 9 eq eq NOUN admet-144 175 10 . . PUNCT admet-144 176 1 ( ( PUNCT admet-144 176 2 4 4 NUM admet-144 176 3 ) ) PUNCT admet-144 176 4 ( ( PUNCT admet-144 176 5 panel panel NOUN admet-144 176 6 b b NOUN admet-144 176 7 ) ) PUNCT admet-144 176 8 . . PUNCT admet-144 177 1 the the DET admet-144 177 2 projected project VERB admet-144 177 3 auc auc ADJ admet-144 177 4 fold fold NOUN admet-144 177 5 - - PUNCT admet-144 177 6 changes change NOUN admet-144 177 7 with with ADP admet-144 177 8 fi fi NOUN admet-144 177 9 , , PUNCT admet-144 177 10 inf inf NOUN admet-144 177 11 = = SYM admet-144 177 12 fi fi NOUN admet-144 177 13 , , PUNCT admet-144 177 14 met meet VERB admet-144 177 15 = = SYM admet-144 177 16 fi fi NOUN admet-144 177 17 , , PUNCT admet-144 177 18 sec sec PROPN admet-144 177 19 = = NOUN admet-144 177 20 0.9 0.9 NUM admet-144 177 21 are be AUX admet-144 177 22 represented represent VERB admet-144 177 23 as as SCONJ admet-144 177 24 follows follow VERB admet-144 177 25 : : PUNCT admet-144 177 26 metabolism metabolism NOUN admet-144 177 27 inhibition inhibition NOUN admet-144 177 28 only only ADV admet-144 177 29 ( ( PUNCT admet-144 177 30 blue blue ADJ admet-144 177 31 bars bar NOUN admet-144 177 32 ) ) PUNCT admet-144 177 33 , , PUNCT admet-144 177 34 exclusive exclusive ADJ admet-144 177 35 sinusoidal sinusoidal NOUN admet-144 177 36 active active ADJ admet-144 177 37 uptake uptake ADJ admet-144 177 38 inhibition inhibition NOUN admet-144 177 39 ( ( PUNCT admet-144 177 40 red red ADJ admet-144 177 41 bars bar NOUN admet-144 177 42 ) ) PUNCT admet-144 177 43 , , PUNCT admet-144 177 44 inhibition inhibition NOUN admet-144 177 45 of of ADP admet-144 177 46 canalicular canalicular ADJ admet-144 177 47 efflux efflux NOUN admet-144 177 48 ( ( PUNCT admet-144 177 49 light light ADJ admet-144 177 50 green green ADJ admet-144 177 51 bars bar NOUN admet-144 177 52 ) ) PUNCT admet-144 177 53 and and CCONJ admet-144 177 54 , , PUNCT admet-144 177 55 simultaneous simultaneous ADJ admet-144 177 56 inhibition inhibition NOUN admet-144 177 57 of of ADP admet-144 177 58 all all DET admet-144 177 59 active active ADJ admet-144 177 60 processes process NOUN admet-144 177 61 together together ADV admet-144 177 62 ( ( PUNCT admet-144 177 63 yellow yellow ADJ admet-144 177 64 bars bar NOUN admet-144 177 65 ) ) PUNCT admet-144 177 66 . . PUNCT admet-144 178 1 neglecting neglect VERB admet-144 178 2 time time NOUN admet-144 178 3 - - PUNCT admet-144 178 4 dependent dependent ADJ admet-144 178 5 concentration concentration NOUN admet-144 178 6 changes change NOUN admet-144 178 7 , , PUNCT admet-144 178 8 static static ADJ admet-144 178 9 ddi ddi NOUN admet-144 178 10 predictions prediction NOUN admet-144 178 11 are be AUX admet-144 178 12 expected expect VERB admet-144 178 13 to to PART admet-144 178 14 provide provide VERB admet-144 178 15 conservative conservative ADJ admet-144 178 16 ( ( PUNCT admet-144 178 17 worst bad ADJ admet-144 178 18 - - PUNCT admet-144 178 19 case case NOUN admet-144 178 20 ) ) PUNCT admet-144 178 21 estimates estimate NOUN admet-144 178 22 for for ADP admet-144 178 23 the the DET admet-144 178 24 effective effective ADJ admet-144 178 25 in in ADP admet-144 178 26 vivo vivo ADJ admet-144 178 27 situation situation NOUN admet-144 178 28 [ [ X admet-144 178 29 1 1 NUM admet-144 178 30 ] ] PUNCT admet-144 178 31 . . PUNCT admet-144 179 1 nevertheless nevertheless ADV admet-144 179 2 , , PUNCT admet-144 179 3 ddi ddi PROPN admet-144 179 4 assessments assessment NOUN admet-144 179 5 according accord VERB admet-144 179 6 to to ADP admet-144 179 7 eq eq PROPN admet-144 179 8 . . PUNCT admet-144 180 1 ( ( PUNCT admet-144 180 2 4 4 X admet-144 180 3 ) ) PUNCT admet-144 180 4 are be AUX admet-144 180 5 generally generally ADV admet-144 180 6 in in ADP admet-144 180 7 good good ADJ admet-144 180 8 agreement agreement NOUN admet-144 180 9 with with ADP admet-144 180 10 clinical clinical ADJ admet-144 180 11 ddi ddi PROPN admet-144 180 12 data datum NOUN admet-144 180 13 for for ADP admet-144 180 14 ecm ecm PROPN admet-144 180 15 class class NOUN admet-144 180 16 1 1 NUM admet-144 180 17 and and CCONJ admet-144 180 18 2 2 NUM admet-144 180 19 compounds compound NOUN admet-144 180 20 as as SCONJ admet-144 180 21 discussed discuss VERB admet-144 180 22 elsewhere elsewhere ADV admet-144 180 23 [ [ X admet-144 180 24 7 7 NUM admet-144 180 25 ] ] PUNCT admet-144 180 26 . . PUNCT admet-144 181 1 however however ADV admet-144 181 2 , , PUNCT admet-144 181 3 with with ADP admet-144 181 4 increasing increase VERB admet-144 181 5 fnren fnren NOUN admet-144 181 6 ( ( PUNCT admet-144 181 7 i.e. i.e. X admet-144 181 8 decreasing decrease VERB admet-144 181 9 fnh fnh PROPN admet-144 181 10 ) ) PUNCT admet-144 181 11 , , PUNCT admet-144 181 12 the the DET admet-144 181 13 predictions prediction NOUN admet-144 181 14 become become VERB admet-144 181 15 less less ADV admet-144 181 16 reliable reliable ADJ admet-144 181 17 for for ADP admet-144 181 18 ecm ecm NOUN admet-144 181 19 class class NOUN admet-144 181 20 3 3 NUM admet-144 181 21 and and CCONJ admet-144 181 22 4 4 NUM admet-144 181 23 compounds compound NOUN admet-144 181 24 , , PUNCT admet-144 181 25 often often ADV admet-144 181 26 resulting result VERB admet-144 181 27 in in ADP admet-144 181 28 significant significant ADJ admet-144 181 29 under under NOUN admet-144 181 30 - - PUNCT admet-144 181 31 estimations estimation NOUN admet-144 181 32 of of ADP admet-144 181 33 the the DET admet-144 181 34 effective effective ADJ admet-144 181 35 ddi ddi ADJ admet-144 181 36 risk risk NOUN admet-144 181 37 observed observe VERB admet-144 181 38 in in ADP admet-144 181 39 clinics clinic NOUN admet-144 181 40 ( ( PUNCT admet-144 181 41 e.g. e.g. ADV admet-144 181 42 pravastatin pravastatin NOUN admet-144 181 43 exposure exposure NOUN admet-144 181 44 in in ADP admet-144 181 45 the the DET admet-144 181 46 presence presence NOUN admet-144 181 47 of of ADP admet-144 181 48 cyclosporine cyclosporine ADJ admet-144 181 49 a a DET admet-144 181 50 ( ( PUNCT admet-144 181 51 inhibitor inhibitor NOUN admet-144 181 52 of of ADP admet-144 181 53 oatp oatp NOUN admet-144 181 54 ’s ’s PART admet-144 181 55 , , PUNCT admet-144 181 56 oat oat NOUN admet-144 181 57 ’s ’s PART admet-144 181 58 , , PUNCT admet-144 181 59 ntcp ntcp PROPN admet-144 181 60 , , PUNCT admet-144 181 61 p p NOUN admet-144 181 62 - - PUNCT admet-144 181 63 gp gp NOUN admet-144 181 64 , , PUNCT admet-144 181 65 bcrp bcrp ADV admet-144 181 66 , , PUNCT admet-144 181 67 mrp2 mrp2 PROPN admet-144 181 68 , , PUNCT admet-144 181 69 cyp3a4 cyp3a4 NOUN admet-144 181 70 and and CCONJ admet-144 181 71 ugt ugt PROPN admet-144 181 72 ’s ’s PART admet-144 181 73 ) ) PUNCT admet-144 181 74 was be AUX admet-144 181 75 reported report VERB admet-144 181 76 to to PART admet-144 181 77 increase increase VERB admet-144 181 78 about about ADV admet-144 181 79 20 20 NUM admet-144 181 80 - - NUM admet-144 181 81 fold fold ADJ admet-144 181 82 , , PUNCT admet-144 181 83 significantly significantly ADV admet-144 181 84 exceeding exceed VERB admet-144 181 85 the the DET admet-144 181 86 theoretically theoretically ADV admet-144 181 87 possible possible ADJ admet-144 181 88 hepatic hepatic ADJ admet-144 181 89 ddi ddi ADJ admet-144 181 90 potential potential NOUN admet-144 181 91 of of ADP admet-144 181 92 2.6 2.6 NUM admet-144 181 93 - - ADJ admet-144 181 94 fold fold ADJ admet-144 181 95 ( ( PUNCT admet-144 181 96 fig fig NOUN admet-144 181 97 . . PUNCT admet-144 181 98 10 10 NUM admet-144 181 99 ) ) PUNCT admet-144 181 100 ) ) PUNCT admet-144 182 1 [ [ X admet-144 182 2 7 7 NUM admet-144 182 3 ] ] PUNCT admet-144 182 4 . . PUNCT admet-144 183 1 the the DET admet-144 183 2 main main ADJ admet-144 183 3 reason reason NOUN admet-144 183 4 for for ADP admet-144 183 5 this this DET admet-144 183 6 observation observation NOUN admet-144 183 7 is be AUX admet-144 183 8 that that SCONJ admet-144 183 9 a a DET admet-144 183 10 significant significant ADJ admet-144 183 11 renal renal ADJ admet-144 183 12 secretion secretion NOUN admet-144 183 13 process process NOUN admet-144 183 14 for for ADP admet-144 183 15 these these DET admet-144 183 16 low low ADJ admet-144 183 17 permeable permeable ADJ admet-144 183 18 camenisch camenisch PROPN admet-144 183 19 et et PROPN admet-144 183 20 al al PROPN admet-144 183 21 . . PROPN admet-144 183 22 admet admet PROPN admet-144 183 23 & & CCONJ admet-144 183 24 dmpk dmpk PROPN admet-144 183 25 3(1 3(1 NUM admet-144 183 26 ) ) PUNCT admet-144 183 27 ( ( PUNCT admet-144 183 28 2015 2015 NUM admet-144 183 29 ) ) PUNCT admet-144 183 30 1 1 NUM admet-144 183 31 - - SYM admet-144 183 32 14 14 NUM admet-144 183 33 12 12 NUM admet-144 183 34 compounds compound NOUN admet-144 183 35 is be AUX admet-144 183 36 typically typically ADV admet-144 183 37 governed govern VERB admet-144 183 38 by by ADP admet-144 183 39 active active ADJ admet-144 183 40 transporter transporter NOUN admet-144 183 41 processes process NOUN admet-144 183 42 which which PRON admet-144 183 43 often often ADV admet-144 183 44 are be AUX admet-144 183 45 concomitantly concomitantly ADV admet-144 183 46 inhibited inhibit VERB admet-144 183 47 by by ADP admet-144 183 48 perpetrator perpetrator NOUN admet-144 183 49 drugs drug NOUN admet-144 183 50 also also ADV admet-144 183 51 interfering interfere VERB admet-144 183 52 with with ADP admet-144 183 53 the the DET admet-144 183 54 sinusoidal sinusoidal NOUN admet-144 183 55 uptake uptake ADJ admet-144 183 56 carrier carrier NOUN admet-144 183 57 system system NOUN admet-144 183 58 in in ADP admet-144 183 59 the the DET admet-144 183 60 liver liver NOUN admet-144 183 61 . . PUNCT admet-144 184 1 consequently consequently ADV admet-144 184 2 , , PUNCT admet-144 184 3 for for ADP admet-144 184 4 conservative conservative ADJ admet-144 184 5 bottom bottom ADJ admet-144 184 6 - - PUNCT admet-144 184 7 up up ADP admet-144 184 8 ddi ddi PROPN admet-144 184 9 estimates estimate VERB admet-144 184 10 the the DET admet-144 184 11 physiologically physiologically ADV admet-144 184 12 less less ADV admet-144 184 13 appropriate appropriate ADJ admet-144 184 14 eq eq ADP admet-144 184 15 . . PUNCT admet-144 185 1 ( ( PUNCT admet-144 185 2 5 5 X admet-144 185 3 ) ) PUNCT admet-144 185 4 should should AUX admet-144 185 5 be be AUX admet-144 185 6 preferred prefer VERB admet-144 185 7 as as SCONJ admet-144 185 8 it it PRON admet-144 185 9 accommodates accommodate VERB admet-144 185 10 for for ADP admet-144 185 11 possible possible ADJ admet-144 185 12 cross cross NOUN admet-144 185 13 - - NOUN admet-144 185 14 reactivity reactivity NOUN admet-144 185 15 on on ADP admet-144 185 16 hepatic hepatic ADJ admet-144 185 17 and and CCONJ admet-144 185 18 renal renal ADJ admet-144 185 19 ( ( PUNCT admet-144 185 20 transporters transporter NOUN admet-144 185 21 ) ) PUNCT admet-144 185 22 systems system NOUN admet-144 185 23 ( ( PUNCT admet-144 185 24 e.g. e.g. ADV admet-144 185 25 the the DET admet-144 185 26 clinical clinical ADJ admet-144 185 27 observation observation NOUN admet-144 185 28 for for ADP admet-144 185 29 pravastatin pravastatin NOUN admet-144 185 30 in in ADP admet-144 185 31 the the DET admet-144 185 32 presence presence NOUN admet-144 185 33 of of ADP admet-144 185 34 cyclosporine cyclosporine PROPN admet-144 185 35 a a PRON admet-144 185 36 is be AUX admet-144 185 37 well well ADV admet-144 185 38 predicted predict VERB admet-144 185 39 with with ADP admet-144 185 40 eq eq NOUN admet-144 185 41 . . PUNCT admet-144 186 1 ( ( PUNCT admet-144 186 2 5 5 NUM admet-144 186 3 ) ) PUNCT admet-144 186 4 ( ( PUNCT admet-144 186 5 fig fig NOUN admet-144 186 6 . . PUNCT admet-144 186 7 10 10 NUM admet-144 186 8 ) ) PUNCT admet-144 186 9 ) ) PUNCT admet-144 186 10 . . PUNCT admet-144 187 1 nevertheless nevertheless ADV admet-144 187 2 , , PUNCT admet-144 187 3 in in ADP admet-144 187 4 combination combination NOUN admet-144 187 5 with with ADP admet-144 187 6 clinical clinical ADJ admet-144 187 7 ddi ddi NOUN admet-144 187 8 data datum NOUN admet-144 187 9 and and CCONJ admet-144 187 10 applying apply VERB admet-144 187 11 a a DET admet-144 187 12 top top ADJ admet-144 187 13 - - PUNCT admet-144 187 14 down down ADP admet-144 187 15 approach approach NOUN admet-144 187 16 , , PUNCT admet-144 187 17 comparative comparative ADJ admet-144 187 18 static static ADJ admet-144 187 19 ddi ddi ADJ admet-144 187 20 assessments assessment NOUN admet-144 187 21 according accord VERB admet-144 187 22 to to ADP admet-144 187 23 eq eq PROPN admet-144 187 24 . . PUNCT admet-144 188 1 ( ( PUNCT admet-144 188 2 4 4 NUM admet-144 188 3 ) ) PUNCT admet-144 188 4 and and CCONJ admet-144 188 5 eq eq NOUN admet-144 188 6 . . PUNCT admet-144 189 1 ( ( PUNCT admet-144 189 2 5 5 X admet-144 189 3 ) ) PUNCT admet-144 189 4 can can AUX admet-144 189 5 be be AUX admet-144 189 6 extremely extremely ADV admet-144 189 7 helpful helpful ADJ admet-144 189 8 in in ADP admet-144 189 9 revealing reveal VERB admet-144 189 10 alternative alternative ADJ admet-144 189 11 ( ( PUNCT admet-144 189 12 extrahepatic extrahepatic ADJ admet-144 189 13 ) ) PUNCT admet-144 189 14 active active ADJ admet-144 189 15 elimination elimination NOUN admet-144 189 16 processes process NOUN admet-144 189 17 as as SCONJ admet-144 189 18 discussed discuss VERB admet-144 189 19 in in ADP admet-144 189 20 full full ADJ admet-144 189 21 detail detail NOUN admet-144 189 22 elsewhere elsewhere ADV admet-144 189 23 [ [ X admet-144 189 24 7 7 NUM admet-144 189 25 ] ] PUNCT admet-144 189 26 . . PUNCT admet-144 190 1 prediction prediction NOUN admet-144 190 2 of of ADP admet-144 190 3 unbound unbound NOUN admet-144 190 4 intracellular intracellular ADJ admet-144 190 5 hepatic hepatic ADJ admet-144 190 6 drug drug NOUN admet-144 190 7 concentrations concentration NOUN admet-144 190 8 figure figure VERB admet-144 190 9 11 11 NUM admet-144 190 10 . . PUNCT admet-144 191 1 ecm ecm NOUN admet-144 191 2 class class NOUN admet-144 191 3 - - PUNCT admet-144 191 4 dependent dependent ADJ admet-144 191 5 effect effect NOUN admet-144 191 6 on on ADP admet-144 191 7 the the DET admet-144 191 8 unbound unbound NOUN admet-144 191 9 liver liver NOUN admet-144 191 10 - - PUNCT admet-144 191 11 to to ADP admet-144 191 12 - - PUNCT admet-144 191 13 capillary capillary ADJ admet-144 191 14 blood blood NOUN admet-144 191 15 concentration concentration NOUN admet-144 191 16 ratio ratio NOUN admet-144 191 17 ( ( PUNCT admet-144 191 18 kpuu kpuu NOUN admet-144 191 19 ) ) PUNCT admet-144 191 20 according accord VERB admet-144 191 21 to to ADP admet-144 191 22 eq eq NOUN admet-144 191 23 . . PROPN admet-144 191 24 6 6 NUM admet-144 191 25 . . PUNCT admet-144 192 1 according accord VERB admet-144 192 2 to to ADP admet-144 192 3 the the DET admet-144 192 4 so so ADV admet-144 192 5 - - PUNCT admet-144 192 6 called call VERB admet-144 192 7 free free ADJ admet-144 192 8 drug drug NOUN admet-144 192 9 hypothesis hypothesis NOUN admet-144 192 10 , , PUNCT admet-144 192 11 at at ADP admet-144 192 12 steady steady ADJ admet-144 192 13 - - PUNCT admet-144 192 14 state state NOUN admet-144 192 15 and and CCONJ admet-144 192 16 in in ADP admet-144 192 17 the the DET admet-144 192 18 absence absence NOUN admet-144 192 19 of of ADP admet-144 192 20 a a DET admet-144 192 21 membrane membrane NOUN admet-144 192 22 transport transport NOUN admet-144 192 23 barrier barrier NOUN admet-144 192 24 limiting limit VERB admet-144 192 25 access access NOUN admet-144 192 26 to to ADP admet-144 192 27 the the DET admet-144 192 28 hepatocyte hepatocyte NOUN admet-144 192 29 , , PUNCT admet-144 192 30 the the DET admet-144 192 31 unbound unbound NOUN admet-144 192 32 ( ( PUNCT admet-144 192 33 free free ADJ admet-144 192 34 ) ) PUNCT admet-144 192 35 intracellular intracellular ADJ admet-144 192 36 concentration concentration NOUN admet-144 192 37 ch ch NOUN admet-144 192 38 , , PUNCT admet-144 192 39 u u NOUN admet-144 192 40 is be AUX admet-144 192 41 equal equal ADJ admet-144 192 42 to to ADP admet-144 192 43 the the DET admet-144 192 44 unbound unbound NOUN admet-144 192 45 blood blood NOUN admet-144 192 46 concentration concentration NOUN admet-144 192 47 cb cb PROPN admet-144 192 48 , , PUNCT admet-144 192 49 u u PROPN admet-144 192 50 ( ( PUNCT admet-144 192 51 i.e. i.e. X admet-144 192 52 ch ch NOUN admet-144 192 53 , , PUNCT admet-144 192 54 u u NOUN admet-144 192 55 / / SYM admet-144 192 56 cb cb PROPN admet-144 192 57 , , PUNCT admet-144 192 58 u u NOUN admet-144 192 59 = = NOUN admet-144 192 60 1 1 NUM admet-144 192 61 ) ) PUNCT admet-144 192 62 . . PUNCT admet-144 193 1 however however ADV admet-144 193 2 , , PUNCT admet-144 193 3 according accord VERB admet-144 193 4 to to ADP admet-144 193 5 the the DET admet-144 193 6 extended extended ADJ admet-144 193 7 clearance clearance NOUN admet-144 193 8 model model NOUN admet-144 193 9 , , PUNCT admet-144 193 10 ch ch PROPN admet-144 193 11 , , PUNCT admet-144 193 12 u u PROPN admet-144 193 13 is be AUX admet-144 193 14 not not PART admet-144 193 15 only only ADV admet-144 193 16 governed govern VERB admet-144 193 17 by by ADP admet-144 193 18 uptake uptake NOUN admet-144 193 19 and and CCONJ admet-144 193 20 protein protein NOUN admet-144 193 21 binding bind VERB admet-144 193 22 but but CCONJ admet-144 193 23 also also ADV admet-144 193 24 by by ADP admet-144 193 25 all all DET admet-144 193 26 intracellular intracellular ADJ admet-144 193 27 elimination elimination NOUN admet-144 193 28 processes process NOUN admet-144 193 29 . . PUNCT admet-144 194 1 therefore therefore ADV admet-144 194 2 , , PUNCT admet-144 194 3 based base VERB admet-144 194 4 on on ADP admet-144 194 5 eq eq ADP admet-144 194 6 . . PUNCT admet-144 195 1 ( ( PUNCT admet-144 195 2 1 1 NUM admet-144 195 3 ) ) PUNCT admet-144 195 4 , , PUNCT admet-144 195 5 for for ADP admet-144 195 6 the the DET admet-144 195 7 liver liver NOUN admet-144 195 8 this this DET admet-144 195 9 relationship relationship NOUN admet-144 195 10 needs need VERB admet-144 195 11 to to PART admet-144 195 12 be be AUX admet-144 195 13 rewritten rewrite VERB admet-144 195 14 as as SCONJ admet-144 195 15 follows follow VERB admet-144 195 16 [ [ X admet-144 195 17 11 11 NUM admet-144 195 18 ] ] SYM admet-144 195 19 : : PUNCT admet-144 195 20 πΆβ„Ž πΆβ„Ž PROPN admet-144 195 21 , , PUNCT admet-144 195 22 𝑒 𝑒 PROPN admet-144 195 23 𝐢𝑏 𝐢𝑏 PROPN admet-144 195 24 , , PUNCT admet-144 195 25 𝑒 𝑒 NOUN admet-144 195 26 = = SYM admet-144 195 27 𝐾𝑝𝑒𝑒 𝐾𝑝𝑒𝑒 PROPN admet-144 195 28 = = SYM admet-144 195 29 𝑃𝑆𝑖𝑛𝑓 𝑃𝑆𝑖𝑛𝑓 PROPN admet-144 195 30 𝑃𝑆𝑒𝑓𝑓 𝑃𝑆𝑒𝑓𝑓 PROPN admet-144 196 1 + + CCONJ admet-144 196 2 𝐢𝐿𝑖𝑛𝑑 𝐢𝐿𝑖𝑛𝑑 PROPN admet-144 196 3 ( ( PUNCT admet-144 196 4 6 6 NUM admet-144 196 5 ) ) PUNCT admet-144 196 6 admet admet PROPN admet-144 196 7 & & CCONJ admet-144 196 8 dmpk dmpk PROPN admet-144 196 9 3(1 3(1 NUM admet-144 196 10 ) ) PUNCT admet-144 196 11 ( ( PUNCT admet-144 196 12 2015 2015 NUM admet-144 196 13 ) ) PUNCT admet-144 196 14 1 1 NUM admet-144 196 15 - - SYM admet-144 196 16 14 14 NUM admet-144 196 17 extended extended ADJ admet-144 196 18 clearance clearance NOUN admet-144 196 19 concept concept NOUN admet-144 196 20 classification classification NOUN admet-144 196 21 system system NOUN admet-144 196 22 ( ( PUNCT admet-144 196 23 ecccs ecccs NOUN admet-144 196 24 ) ) PUNCT admet-144 196 25 doi doi NOUN admet-144 196 26 : : PUNCT admet-144 196 27 10.5599 10.5599 NUM admet-144 196 28 / / SYM admet-144 196 29 admet.3.1.144 admet.3.1.144 PROPN admet-144 196 30 13 13 NUM admet-144 196 31 where where SCONJ admet-144 196 32 , , PUNCT admet-144 196 33 kpuu kpuu NOUN admet-144 196 34 is be AUX admet-144 196 35 the the DET admet-144 196 36 unbound unbound ADJ admet-144 196 37 liver liver NOUN admet-144 196 38 - - PUNCT admet-144 196 39 to to ADP admet-144 196 40 - - PUNCT admet-144 196 41 capillary capillary ADJ admet-144 196 42 blood blood NOUN admet-144 196 43 concentration concentration NOUN admet-144 196 44 ratio ratio NOUN admet-144 196 45 . . PUNCT admet-144 197 1 in in ADP admet-144 197 2 line line NOUN admet-144 197 3 with with ADP admet-144 197 4 ecm ecm NOUN admet-144 197 5 , , PUNCT admet-144 197 6 the the DET admet-144 197 7 impact impact NOUN admet-144 197 8 of of ADP admet-144 197 9 the the DET admet-144 197 10 relative relative ADJ admet-144 197 11 process process NOUN admet-144 197 12 contributions contribution NOUN admet-144 197 13 on on ADP admet-144 197 14 kpuu kpuu NOUN admet-144 197 15 can can AUX admet-144 197 16 be be AUX admet-144 197 17 summarized summarize VERB admet-144 197 18 as as SCONJ admet-144 197 19 shown show VERB admet-144 197 20 in in ADP admet-144 197 21 fig fig NOUN admet-144 197 22 . . PUNCT admet-144 198 1 11 11 NUM admet-144 198 2 . . PUNCT admet-144 199 1 the the DET admet-144 199 2 knowledge knowledge NOUN admet-144 199 3 of of ADP admet-144 199 4 the the DET admet-144 199 5 relevant relevant ADJ admet-144 199 6 ( ( PUNCT admet-144 199 7 effective effective ADJ admet-144 199 8 ) ) PUNCT admet-144 199 9 intrahepatic intrahepatic ADJ admet-144 199 10 concentrations concentration NOUN admet-144 199 11 is be AUX admet-144 199 12 important important ADJ admet-144 199 13 when when SCONJ admet-144 199 14 performing perform VERB admet-144 199 15 ddi ddi ADJ admet-144 199 16 risk risk NOUN admet-144 199 17 assessments assessment NOUN admet-144 199 18 ( ( PUNCT admet-144 199 19 compound compound NOUN admet-144 199 20 acting act VERB admet-144 199 21 as as ADP admet-144 199 22 inhibitor inhibitor NOUN admet-144 199 23 ) ) PUNCT admet-144 199 24 on on ADP admet-144 199 25 active active ADJ admet-144 199 26 processes process NOUN admet-144 199 27 such such ADJ admet-144 199 28 as as ADP admet-144 199 29 metabolism metabolism NOUN admet-144 199 30 and/or and/or CCONJ admet-144 199 31 canalicular canalicular ADJ admet-144 199 32 efflux efflux NOUN admet-144 199 33 . . PUNCT admet-144 200 1 however however ADV admet-144 200 2 , , PUNCT admet-144 200 3 due due ADP admet-144 200 4 to to ADP admet-144 200 5 experimental experimental ADJ admet-144 200 6 inaccessibility inaccessibility NOUN admet-144 200 7 of of ADP admet-144 200 8 ch ch PROPN admet-144 200 9 , , PUNCT admet-144 200 10 u u NOUN admet-144 200 11 , , PUNCT admet-144 200 12 static static ADJ admet-144 200 13 perpetrator perpetrator NOUN admet-144 200 14 risk risk NOUN admet-144 200 15 calculations calculation NOUN admet-144 200 16 for for ADP admet-144 200 17 the the DET admet-144 200 18 liver liver NOUN admet-144 200 19 generally generally ADV admet-144 200 20 refer refer VERB admet-144 200 21 to to ADP admet-144 200 22 cb cb PROPN admet-144 200 23 , , PUNCT admet-144 200 24 u u PROPN admet-144 200 25 ( ( PUNCT admet-144 200 26 usually usually ADV admet-144 200 27 expressed express VERB admet-144 200 28 as as ADP admet-144 200 29 cb cb PROPN admet-144 200 30 , , PUNCT admet-144 200 31 u u NOUN admet-144 200 32 /ki /ki ADP admet-144 200 33 , , PUNCT admet-144 200 34 where where SCONJ admet-144 200 35 ki ki PROPN admet-144 200 36 denotes denote VERB admet-144 200 37 the the DET admet-144 200 38 inhibition inhibition NOUN admet-144 200 39 constant constant ADJ admet-144 200 40 on on ADP admet-144 200 41 a a DET admet-144 200 42 particular particular ADJ admet-144 200 43 process process NOUN admet-144 200 44 ) ) PUNCT admet-144 200 45 . . PUNCT admet-144 201 1 based base VERB admet-144 201 2 on on ADP admet-144 201 3 the the DET admet-144 201 4 extended extend VERB admet-144 201 5 clearance clearance NOUN admet-144 201 6 model model NOUN admet-144 201 7 it it PRON admet-144 201 8 becomes become VERB admet-144 201 9 evident evident ADJ admet-144 201 10 that that SCONJ admet-144 201 11 the the DET admet-144 201 12 use use NOUN admet-144 201 13 of of ADP admet-144 201 14 this this DET admet-144 201 15 substitute substitute NOUN admet-144 201 16 might might AUX admet-144 201 17 lead lead VERB admet-144 201 18 to to ADP admet-144 201 19 a a DET admet-144 201 20 considerable considerable ADJ admet-144 201 21 misjudgment misjudgment NOUN admet-144 201 22 of of ADP admet-144 201 23 the the DET admet-144 201 24 ddi ddi PROPN admet-144 201 25 potential potential NOUN admet-144 201 26 of of ADP admet-144 201 27 perpetrator perpetrator NOUN admet-144 201 28 drugs drug NOUN admet-144 201 29 though though ADV admet-144 201 30 . . PUNCT admet-144 202 1 depending depend VERB admet-144 202 2 on on ADP admet-144 202 3 the the DET admet-144 202 4 major major ADJ admet-144 202 5 ratedetermining ratedetermining NOUN admet-144 202 6 process process NOUN admet-144 202 7 driving drive VERB admet-144 202 8 hepatic hepatic ADJ admet-144 202 9 elimination elimination NOUN admet-144 202 10 significant significant ADJ admet-144 202 11 under(e.g under(e.g PROPN admet-144 202 12 . . PUNCT admet-144 203 1 kpuu kpuu NOUN admet-144 203 2 equals equal VERB admet-144 203 3 2.4 2.4 NUM admet-144 203 4 for for ADP admet-144 203 5 ecm ecm NOUN admet-144 203 6 class class NOUN admet-144 203 7 4 4 NUM admet-144 203 8 compound compound NOUN admet-144 203 9 pravastatin pravastatin NOUN admet-144 203 10 ) ) PUNCT admet-144 203 11 or or CCONJ admet-144 203 12 over(e.g over(e.g PROPN admet-144 203 13 . . PROPN admet-144 203 14 ch ch PROPN admet-144 203 15 , , PUNCT admet-144 203 16 u u NOUN admet-144 203 17 is be AUX admet-144 203 18 about about ADV admet-144 203 19 80 80 NUM admet-144 203 20 - - NOUN admet-144 203 21 fold fold VERB admet-144 203 22 less less ADV admet-144 203 23 than than ADP admet-144 203 24 cb cb PROPN admet-144 203 25 , , PUNCT admet-144 203 26 u u NOUN admet-144 203 27 for for ADP admet-144 203 28 ecm ecm PROPN admet-144 203 29 class class NOUN admet-144 203 30 3 3 NUM admet-144 203 31 compound compound NOUN admet-144 203 32 cimetidine cimetidine NOUN admet-144 203 33 ) ) PUNCT admet-144 204 1 estimations estimation NOUN admet-144 204 2 of of ADP admet-144 204 3 the the DET admet-144 204 4 real real ADJ admet-144 204 5 interaction interaction NOUN admet-144 204 6 risk risk NOUN admet-144 204 7 might might AUX admet-144 204 8 result result VERB admet-144 204 9 . . PUNCT admet-144 205 1 the the DET admet-144 205 2 use use NOUN admet-144 205 3 of of ADP admet-144 205 4 systemic systemic ADJ admet-144 205 5 unbound unbound NOUN admet-144 205 6 drug drug NOUN admet-144 205 7 concentrations concentration NOUN admet-144 205 8 ( ( PUNCT admet-144 205 9 or or CCONJ admet-144 205 10 unbound unbound NOUN admet-144 205 11 drug drug NOUN admet-144 205 12 concentrations concentration NOUN admet-144 205 13 in in ADP admet-144 205 14 the the DET admet-144 205 15 portal portal ADJ admet-144 205 16 vein vein NOUN admet-144 205 17 ) ) PUNCT admet-144 205 18 is be AUX admet-144 205 19 thus thus ADV admet-144 205 20 likely likely ADV admet-144 205 21 insufficient insufficient ADJ admet-144 205 22 to to PART admet-144 205 23 properly properly ADV admet-144 205 24 assess assess VERB admet-144 205 25 the the DET admet-144 205 26 actual actual ADJ admet-144 205 27 drug drug NOUN admet-144 205 28 - - PUNCT admet-144 205 29 drug drug NOUN admet-144 205 30 interaction interaction NOUN admet-144 205 31 potential potential NOUN admet-144 205 32 on on ADP admet-144 205 33 intracellular intracellular ADJ admet-144 205 34 enzymes enzyme NOUN admet-144 205 35 / / SYM admet-144 205 36 transporters transporter NOUN admet-144 205 37 for for ADP admet-144 205 38 class class NOUN admet-144 205 39 1 1 NUM admet-144 205 40 , , PUNCT admet-144 205 41 3 3 NUM admet-144 205 42 and and CCONJ admet-144 205 43 4 4 NUM admet-144 205 44 compounds compound NOUN admet-144 205 45 as as SCONJ admet-144 205 46 illustrated illustrate VERB admet-144 205 47 in in ADP admet-144 205 48 table table NOUN admet-144 205 49 2 2 NUM admet-144 205 50 . . PUNCT admet-144 205 51 table table NOUN admet-144 205 52 2 2 NUM admet-144 205 53 . . PUNCT admet-144 205 54 effect effect NOUN admet-144 205 55 of of ADP admet-144 205 56 kpuu kpuu NOUN admet-144 205 57 on on ADP admet-144 205 58 ch ch PROPN admet-144 205 59 , , PUNCT admet-144 205 60 u u NOUN admet-144 205 61 and and CCONJ admet-144 205 62 the the DET admet-144 205 63 ddi ddi PROPN admet-144 205 64 risk risk NOUN admet-144 205 65 outcome outcome NOUN admet-144 205 66 for for ADP admet-144 205 67 perpetrator perpetrator NOUN admet-144 205 68 drugs drug NOUN admet-144 205 69 . . PUNCT admet-144 206 1 ecm ecm NOUN admet-144 206 2 class class NOUN admet-144 206 3 effect effect NOUN admet-144 206 4 of of ADP admet-144 206 5 kpuu kpuu NOUN admet-144 206 6 on on ADP admet-144 206 7 ch ch PROPN admet-144 206 8 , , PUNCT admet-144 206 9 u u NOUN admet-144 206 10 ( ( PUNCT admet-144 206 11 eq eq NOUN admet-144 206 12 . . PUNCT admet-144 207 1 ( ( PUNCT admet-144 207 2 6 6 NUM admet-144 207 3 ) ) PUNCT admet-144 207 4 ) ) PUNCT admet-144 207 5 risk risk NOUN admet-144 207 6 assessment assessment NOUN admet-144 207 7 with with ADP admet-144 207 8 cb cb PROPN admet-144 207 9 , , PUNCT admet-144 207 10 u u NOUN admet-144 207 11 /ki /ki PUNCT admet-144 207 12 1 1 NUM admet-144 207 13 ch ch NOUN admet-144 207 14 , , PUNCT admet-144 207 15 u u NOUN admet-144 207 16 < < X admet-144 207 17 < < X admet-144 207 18 cb cb PROPN admet-144 207 19 , , PUNCT admet-144 207 20 u u NOUN admet-144 207 21 overestimation overestimation NOUN admet-144 207 22 2 2 NUM admet-144 207 23 ch ch NOUN admet-144 207 24 , , PUNCT admet-144 207 25 u u NOUN admet-144 207 26 = = SYM admet-144 207 27 cb cb PROPN admet-144 207 28 , , PUNCT admet-144 207 29 u u NOUN admet-144 207 30 predictive predictive ADJ admet-144 207 31 3 3 NUM admet-144 207 32 ch ch NOUN admet-144 207 33 , , PUNCT admet-144 207 34 u u NOUN admet-144 207 35 < < X admet-144 207 36 or or CCONJ admet-144 207 37 > > X admet-144 207 38 cb cb PROPN admet-144 207 39 , , PUNCT admet-144 207 40 u u NOUN admet-144 207 41 underor underor NOUN admet-144 207 42 overestimation overestimation NOUN admet-144 207 43 ( ( PUNCT admet-144 207 44 generally generally ADV admet-144 207 45 overestimation overestimation NOUN admet-144 207 46 as as ADP admet-144 207 47 usually usually ADV admet-144 207 48 psinf psinf VERB admet-144 207 49 < < X admet-144 207 50 clint clint NOUN admet-144 207 51 ) ) PUNCT admet-144 207 52 4 4 NUM admet-144 207 53 ch ch NOUN admet-144 207 54 , , PUNCT admet-144 207 55 u u NOUN admet-144 207 56 < < X admet-144 207 57 or or CCONJ admet-144 207 58 > > X admet-144 207 59 cb cb PROPN admet-144 207 60 , , PUNCT admet-144 207 61 u u NOUN admet-144 207 62 underor underor NOUN admet-144 207 63 overestimation overestimation NOUN admet-144 207 64 ( ( PUNCT admet-144 207 65 generally generally ADV admet-144 207 66 underestimation underestimation ADJ admet-144 207 67 as as ADP admet-144 207 68 usually usually ADV admet-144 207 69 psinf psinf ADJ admet-144 207 70 > > X admet-144 207 71 pseff pseff NOUN admet-144 207 72 ) ) PUNCT admet-144 207 73 although although SCONJ admet-144 207 74 currently currently ADV admet-144 207 75 not not PART admet-144 207 76 requested request VERB admet-144 207 77 by by ADP admet-144 207 78 health health NOUN admet-144 207 79 authorities authority NOUN admet-144 207 80 present present VERB admet-144 207 81 ecm ecm NOUN admet-144 207 82 - - PUNCT admet-144 207 83 based base VERB admet-144 207 84 principles principle NOUN admet-144 207 85 might might AUX admet-144 207 86 change change VERB admet-144 207 87 the the DET admet-144 207 88 way way NOUN admet-144 207 89 we we PRON admet-144 207 90 are be AUX admet-144 207 91 doing do VERB admet-144 207 92 perpetrator perpetrator NOUN admet-144 207 93 ddi ddi ADJ admet-144 207 94 risk risk NOUN admet-144 207 95 assessments assessment NOUN admet-144 207 96 for for ADP admet-144 207 97 intracellular intracellular ADJ admet-144 207 98 hepatic hepatic ADJ admet-144 207 99 processes process NOUN admet-144 207 100 in in ADP admet-144 207 101 the the DET admet-144 207 102 future future NOUN admet-144 207 103 , , PUNCT admet-144 207 104 all all DET admet-144 207 105 the the PRON admet-144 207 106 more more ADV admet-144 207 107 the the DET admet-144 207 108 mechanistic mechanistic ADJ admet-144 207 109 ivive ivive ADJ admet-144 207 110 method method NOUN admet-144 207 111 presented present VERB admet-144 207 112 in in ADP admet-144 207 113 this this DET admet-144 207 114 manuscript manuscript NOUN admet-144 207 115 was be AUX admet-144 207 116 demonstrated demonstrate VERB admet-144 207 117 to to PART admet-144 207 118 provide provide VERB admet-144 207 119 quantitative quantitative ADJ admet-144 207 120 reliable reliable ADJ admet-144 207 121 estimates estimate NOUN admet-144 207 122 of of ADP admet-144 207 123 clh clh PROPN admet-144 207 124 , , PUNCT admet-144 207 125 obs obs PROPN admet-144 207 126 and and CCONJ admet-144 207 127 therewith therewith NOUN admet-144 207 128 of of ADP admet-144 207 129 kpuu kpuu NOUN admet-144 207 130 ( ( PUNCT admet-144 207 131 see see VERB admet-144 207 132 above above ADV admet-144 207 133 ) ) PUNCT admet-144 207 134 . . PUNCT admet-144 208 1 further far ADV admet-144 208 2 in in ADP admet-144 208 3 - - PUNCT admet-144 208 4 house house NOUN admet-144 208 5 research research NOUN admet-144 208 6 on on ADP admet-144 208 7 this this PRON admet-144 208 8 this this DET admet-144 208 9 topic topic NOUN admet-144 208 10 is be AUX admet-144 208 11 currently currently ADV admet-144 208 12 ongoing ongoing ADJ admet-144 208 13 . . PUNCT admet-144 209 1 conclusions conclusion NOUN admet-144 209 2 in in ADP admet-144 209 3 this this DET admet-144 209 4 review review NOUN admet-144 209 5 , , PUNCT admet-144 209 6 we we PRON admet-144 209 7 have have AUX admet-144 209 8 illustrated illustrate VERB admet-144 209 9 the the DET admet-144 209 10 usefulness usefulness NOUN admet-144 209 11 of of ADP admet-144 209 12 the the DET admet-144 209 13 extended extended ADJ admet-144 209 14 clearance clearance NOUN admet-144 209 15 model model NOUN admet-144 209 16 for for ADP admet-144 209 17 classifying classify VERB admet-144 209 18 drug drug NOUN admet-144 209 19 compounds compound NOUN admet-144 209 20 depending depend VERB admet-144 209 21 on on ADP admet-144 209 22 the the DET admet-144 209 23 relative relative ADJ admet-144 209 24 contributions contribution NOUN admet-144 209 25 of of ADP admet-144 209 26 the the DET admet-144 209 27 individual individual ADJ admet-144 209 28 hepatic hepatic ADJ admet-144 209 29 elimination elimination NOUN admet-144 209 30 processes process NOUN admet-144 209 31 . . PUNCT admet-144 210 1 the the DET admet-144 210 2 ecm ecm PROPN admet-144 210 3 classification classification NOUN admet-144 210 4 system system NOUN admet-144 210 5 based base VERB admet-144 210 6 upon upon SCONJ admet-144 210 7 easily easily ADV admet-144 210 8 accessible accessible ADJ admet-144 210 9 in in ADP admet-144 210 10 vitro vitro X admet-144 210 11 data datum NOUN admet-144 210 12 for for ADP admet-144 210 13 metabolism metabolism NOUN admet-144 210 14 , , PUNCT admet-144 210 15 sinusoidal sinusoidal NOUN admet-144 210 16 transport transport NOUN admet-144 210 17 and and CCONJ admet-144 210 18 canalicular canalicular ADJ admet-144 210 19 efflux efflux NOUN admet-144 210 20 allows allow VERB admet-144 210 21 the the DET admet-144 210 22 quantitative quantitative ADJ admet-144 210 23 bottom bottom ADJ admet-144 210 24 - - PUNCT admet-144 210 25 up up ADP admet-144 210 26 assessment assessment NOUN admet-144 210 27 of of ADP admet-144 210 28 a a DET admet-144 210 29 series series NOUN admet-144 210 30 of of ADP admet-144 210 31 ( ( PUNCT admet-144 210 32 pharmacokinetic pharmacokinetic ADJ admet-144 210 33 ) ) PUNCT admet-144 210 34 parameters parameter NOUN admet-144 210 35 such such ADJ admet-144 210 36 as as ADP admet-144 210 37 the the DET admet-144 210 38 hepatic hepatic ADJ admet-144 210 39 clearance clearance NOUN admet-144 210 40 , , PUNCT admet-144 210 41 the the DET admet-144 210 42 unbound unbound NOUN admet-144 210 43 liver liver NOUN admet-144 210 44 - - PUNCT admet-144 210 45 to to ADP admet-144 210 46 - - PUNCT admet-144 210 47 capillary capillary ADJ admet-144 210 48 blood blood NOUN admet-144 210 49 concentration concentration NOUN admet-144 210 50 ratio ratio NOUN admet-144 210 51 and and CCONJ admet-144 210 52 the the DET admet-144 210 53 static static ADJ admet-144 210 54 prediction prediction NOUN admet-144 210 55 of of ADP admet-144 210 56 the the DET admet-144 210 57 ddi ddi PROPN admet-144 210 58 potential potential NOUN admet-144 210 59 of of ADP admet-144 210 60 drug drug NOUN admet-144 210 61 molecules molecule NOUN admet-144 210 62 . . PUNCT admet-144 211 1 the the DET admet-144 211 2 method method NOUN admet-144 211 3 reveals reveal VERB admet-144 211 4 the the DET admet-144 211 5 major major ADJ admet-144 211 6 role role NOUN admet-144 211 7 of of ADP admet-144 211 8 sinusoidal sinusoidal NOUN admet-144 211 9 uptake uptake ADJ admet-144 211 10 as as ADP admet-144 211 11 a a DET admet-144 211 12 gatekeeper gatekeeper NOUN admet-144 211 13 for for ADP admet-144 211 14 drug drug NOUN admet-144 211 15 elimination elimination NOUN admet-144 211 16 , , PUNCT admet-144 211 17 provides provide VERB admet-144 211 18 insight insight NOUN admet-144 211 19 into into ADP admet-144 211 20 the the DET admet-144 211 21 performance performance NOUN admet-144 211 22 of of ADP admet-144 211 23 different different ADJ admet-144 211 24 ivive ivive ADJ admet-144 211 25 approaches approach NOUN admet-144 211 26 for for ADP admet-144 211 27 hepatic hepatic ADJ admet-144 211 28 clearance clearance NOUN admet-144 211 29 prediction prediction NOUN admet-144 211 30 and and CCONJ admet-144 211 31 highlights highlight VERB admet-144 211 32 potential potential ADJ admet-144 211 33 limitations limitation NOUN admet-144 211 34 of of ADP admet-144 211 35 currently currently ADV admet-144 211 36 applied apply VERB admet-144 211 37 drugdrug drugdrug NOUN admet-144 211 38 interaction interaction NOUN admet-144 211 39 risk risk NOUN admet-144 211 40 assessment assessment NOUN admet-144 211 41 approaches approach NOUN admet-144 211 42 . . PUNCT admet-144 212 1 consequently consequently ADV admet-144 212 2 , , PUNCT admet-144 212 3 following follow VERB admet-144 212 4 a a DET admet-144 212 5 thoughtful thoughtful ADJ admet-144 212 6 implementation implementation NOUN admet-144 212 7 , , PUNCT admet-144 212 8 the the DET admet-144 212 9 approach approach NOUN admet-144 212 10 may may AUX admet-144 212 11 facilitate facilitate VERB admet-144 212 12 the the DET admet-144 212 13 compound compound NOUN admet-144 212 14 selection selection NOUN admet-144 212 15 process process NOUN admet-144 212 16 in in ADP admet-144 212 17 pharmaceutical pharmaceutical ADJ admet-144 212 18 research research NOUN admet-144 212 19 and and CCONJ admet-144 212 20 improve improve VERB admet-144 212 21 some some PRON admet-144 212 22 of of ADP admet-144 212 23 the the DET admet-144 212 24 compound compound NOUN admet-144 212 25 profiling profiling NOUN admet-144 212 26 methodologies methodology NOUN admet-144 212 27 ( ( PUNCT admet-144 212 28 e.g. e.g. ADV admet-144 212 29 ddi ddi ADJ admet-144 212 30 risk risk NOUN admet-144 212 31 assessment assessment NOUN admet-144 212 32 ) ) PUNCT admet-144 212 33 applied apply VERB admet-144 212 34 in in ADP admet-144 212 35 drug drug NOUN admet-144 212 36 development development NOUN admet-144 212 37 . . PUNCT admet-144 213 1 camenisch camenisch PROPN admet-144 213 2 et et PROPN admet-144 213 3 al al PROPN admet-144 213 4 . . PROPN admet-144 213 5 admet admet PROPN admet-144 213 6 & & CCONJ admet-144 213 7 dmpk dmpk PROPN admet-144 213 8 3(1 3(1 NUM admet-144 213 9 ) ) PUNCT admet-144 213 10 ( ( PUNCT admet-144 213 11 2015 2015 NUM admet-144 213 12 ) ) PUNCT admet-144 213 13 1 1 NUM admet-144 213 14 - - SYM admet-144 213 15 14 14 NUM admet-144 213 16 14 14 NUM admet-144 213 17 acknowledgements acknowledgement NOUN admet-144 213 18 : : PUNCT admet-144 213 19 the the DET admet-144 213 20 author author NOUN admet-144 213 21 wishes wish VERB admet-144 213 22 to to PART admet-144 213 23 acknowledge acknowledge VERB admet-144 213 24 the the DET admet-144 213 25 many many ADJ admet-144 213 26 novartis novartis NOUN admet-144 213 27 drug drug NOUN admet-144 213 28 metabolism metabolism NOUN admet-144 213 29 and and CCONJ admet-144 213 30 pharmacokinetic pharmacokinetic ADJ admet-144 213 31 scientists scientist NOUN admet-144 213 32 of of ADP admet-144 213 33 basel basel PROPN admet-144 213 34 , , PUNCT admet-144 213 35 switzerland switzerland PROPN admet-144 213 36 , , PUNCT admet-144 213 37 who who PRON admet-144 213 38 have have AUX admet-144 213 39 supported support VERB admet-144 213 40 this this DET admet-144 213 41 work work NOUN admet-144 213 42 . . PUNCT admet-144 214 1 special special ADJ admet-144 214 2 thanks thank NOUN admet-144 214 3 go go VERB admet-144 214 4 to to ADP admet-144 214 5 dr dr PROPN admet-144 214 6 markus markus PROPN admet-144 214 7 zollinger zollinger NOUN admet-144 214 8 for for ADP admet-144 214 9 his his PRON admet-144 214 10 critical critical ADJ admet-144 214 11 evaluation evaluation NOUN admet-144 214 12 of of ADP admet-144 214 13 this this DET admet-144 214 14 manuscript manuscript NOUN admet-144 214 15 . . PUNCT admet-144 215 1 references reference NOUN admet-144 215 2 [ [ X admet-144 215 3 1 1 NUM admet-144 215 4 ] ] X admet-144 215 5 g. g. PROPN admet-144 215 6 camenisch camenisch PROPN admet-144 215 7 and and CCONJ admet-144 215 8 k. k. PROPN admet-144 215 9 umehara umehara PROPN admet-144 215 10 , , PUNCT admet-144 215 11 biopharmaceutics biopharmaceutics PROPN admet-144 215 12 & & CCONJ admet-144 215 13 drug drug PROPN admet-144 215 14 disposition disposition NOUN admet-144 215 15 33 33 NUM admet-144 215 16 ( ( PUNCT admet-144 215 17 2012 2012 NUM admet-144 215 18 ) ) PUNCT admet-144 215 19 179 179 NUM admet-144 215 20 - - SYM admet-144 215 21 1940 1940 NUM admet-144 215 22 . . PUNCT admet-144 216 1 [ [ X admet-144 216 2 2 2 NUM admet-144 216 3 ] ] X admet-144 216 4 y. y. PROPN admet-144 216 5 shitara shitara PROPN admet-144 216 6 , , PUNCT admet-144 216 7 h. h. PROPN admet-144 216 8 sato sato PROPN admet-144 216 9 and and CCONJ admet-144 216 10 y. y. PROPN admet-144 216 11 sugiyama sugiyama PROPN admet-144 216 12 , , PUNCT admet-144 216 13 annual annual ADJ admet-144 216 14 review review NOUN admet-144 216 15 of of ADP admet-144 216 16 pharmacology pharmacology NOUN admet-144 216 17 and and CCONJ admet-144 216 18 toxicology toxicology NOUN admet-144 216 19 45 45 NUM admet-144 216 20 ( ( PUNCT admet-144 216 21 2005 2005 NUM admet-144 216 22 ) ) PUNCT admet-144 216 23 689723 689723 NUM admet-144 216 24 . . PUNCT admet-144 217 1 [ [ X admet-144 217 2 3 3 X admet-144 217 3 ] ] PUNCT admet-144 217 4 k. k. PROPN admet-144 217 5 umehara umehara PROPN admet-144 217 6 and and CCONJ admet-144 217 7 g. g. PROPN admet-144 217 8 camenisch camenisch PROPN admet-144 217 9 , , PUNCT admet-144 217 10 pharmaceutical pharmaceutical ADJ admet-144 217 11 research research NOUN admet-144 217 12 29 29 NUM admet-144 217 13 ( ( PUNCT admet-144 217 14 2012 2012 NUM admet-144 217 15 ) ) PUNCT admet-144 217 16 603 603 NUM admet-144 217 17 - - SYM admet-144 217 18 617 617 NUM admet-144 217 19 . . PUNCT admet-144 218 1 [ [ X admet-144 218 2 4 4 NUM admet-144 218 3 ] ] PUNCT admet-144 218 4 a. a. NOUN admet-144 218 5 kunze kunze PROPN admet-144 218 6 , , PUNCT admet-144 218 7 b. b. PROPN admet-144 218 8 poller poller PROPN admet-144 218 9 , , PUNCT admet-144 218 10 j. j. PROPN admet-144 218 11 huwyler huwyler PROPN admet-144 218 12 and and CCONJ admet-144 218 13 g. g. PROPN admet-144 218 14 camenisch camenisch PROPN admet-144 218 15 , , PUNCT admet-144 218 16 drug drug NOUN admet-144 218 17 metabolism metabolism NOUN admet-144 218 18 and and CCONJ admet-144 218 19 drug drug NOUN admet-144 218 20 interactions interaction NOUN admet-144 218 21 in in ADP admet-144 218 22 press press NOUN admet-144 218 23 . . PUNCT admet-144 219 1 [ [ X admet-144 219 2 5 5 X admet-144 219 3 ] ] PUNCT admet-144 219 4 d. d. PROPN admet-144 219 5 mcginnity mcginnity PROPN admet-144 219 6 , , PUNCT admet-144 219 7 m. m. NOUN admet-144 219 8 soars soar NOUN admet-144 219 9 , , PUNCT admet-144 219 10 r. r. PROPN admet-144 219 11 urbanowicz urbanowicz PROPN admet-144 219 12 and and CCONJ admet-144 219 13 r. r. PROPN admet-144 219 14 riley riley PROPN admet-144 219 15 , , PUNCT admet-144 219 16 drug drug NOUN admet-144 219 17 metabolism metabolism NOUN admet-144 219 18 and and CCONJ admet-144 219 19 disposition disposition NOUN admet-144 219 20 32 32 NUM admet-144 219 21 ( ( PUNCT admet-144 219 22 2004 2004 NUM admet-144 219 23 ) ) PUNCT admet-144 219 24 1247 1247 NUM admet-144 219 25 - - SYM admet-144 219 26 1253 1253 NUM admet-144 219 27 . . PUNCT admet-144 220 1 [ [ X admet-144 220 2 6 6 NUM admet-144 220 3 ] ] PUNCT admet-144 220 4 d. d. PROPN admet-144 220 5 hallifax hallifax PROPN admet-144 220 6 , , PUNCT admet-144 220 7 e. e. PROPN admet-144 220 8 turlizzi turlizzi PROPN admet-144 220 9 , , PUNCT admet-144 220 10 u. u. PROPN admet-144 220 11 zanelli zanelli PROPN admet-144 220 12 and and CCONJ admet-144 220 13 j. j. PROPN admet-144 220 14 houston houston PROPN admet-144 220 15 , , PUNCT admet-144 220 16 european european PROPN admet-144 220 17 journal journal PROPN admet-144 220 18 of of ADP admet-144 220 19 pharmaceutical pharmaceutical PROPN admet-144 220 20 sciences science NOUN admet-144 220 21 45 45 NUM admet-144 220 22 ( ( PUNCT admet-144 220 23 2012 2012 NUM admet-144 220 24 ) ) PUNCT admet-144 220 25 570 570 NUM admet-144 220 26 - - SYM admet-144 220 27 574 574 NUM admet-144 220 28 . . PUNCT admet-144 221 1 [ [ X admet-144 221 2 7 7 NUM admet-144 221 3 ] ] PUNCT admet-144 221 4 a. a. NOUN admet-144 221 5 kunze kunze PROPN admet-144 221 6 , , PUNCT admet-144 221 7 j. j. PROPN admet-144 221 8 huwyler huwyler PROPN admet-144 221 9 , , PUNCT admet-144 221 10 b. b. PROPN admet-144 221 11 poller poller PROPN admet-144 221 12 , , PUNCT admet-144 221 13 h. h. PROPN admet-144 221 14 gutmann gutmann PROPN admet-144 221 15 and and CCONJ admet-144 221 16 g. g. PROPN admet-144 221 17 camenisch camenisch PROPN admet-144 221 18 , , PUNCT admet-144 221 19 journal journal NOUN admet-144 221 20 of of ADP admet-144 221 21 pharmaceutical pharmaceutical PROPN admet-144 221 22 sciences science NOUN admet-144 221 23 103 103 NUM admet-144 221 24 ( ( PUNCT admet-144 221 25 2014 2014 NUM admet-144 221 26 ) ) PUNCT admet-144 221 27 994 994 NUM admet-144 221 28 - - SYM admet-144 221 29 1001 1001 NUM admet-144 221 30 . . PUNCT admet-144 222 1 [ [ X admet-144 222 2 8 8 NUM admet-144 222 3 ] ] X admet-144 222 4 l. l. PROPN admet-144 222 5 benet benet PROPN admet-144 222 6 , , PUNCT admet-144 222 7 g. g. PROPN admet-144 222 8 amidon amidon PROPN admet-144 222 9 , , PUNCT admet-144 222 10 d. d. PROPN admet-144 222 11 barends barends PROPN admet-144 222 12 , , PUNCT admet-144 222 13 h. h. PROPN admet-144 222 14 lennernas lennernas PROPN admet-144 222 15 , , PUNCT admet-144 222 16 j. j. PROPN admet-144 222 17 polli polli PROPN admet-144 222 18 , , PUNCT admet-144 222 19 v. v. ADP admet-144 222 20 shah shah PROPN admet-144 222 21 , , PUNCT admet-144 222 22 s. s. PROPN admet-144 222 23 stavchansky stavchansky PROPN admet-144 222 24 and and CCONJ admet-144 222 25 l. l. PROPN admet-144 222 26 yu yu PROPN admet-144 222 27 , , PUNCT admet-144 222 28 pharmaceutical pharmaceutical ADJ admet-144 222 29 research research NOUN admet-144 222 30 25 25 NUM admet-144 222 31 ( ( PUNCT admet-144 222 32 2008 2008 NUM admet-144 222 33 ) ) PUNCT admet-144 222 34 483 483 NUM admet-144 222 35 - - SYM admet-144 222 36 48 48 NUM admet-144 222 37 . . PUNCT admet-144 223 1 [ [ X admet-144 223 2 9 9 NUM admet-144 223 3 ] ] PUNCT admet-144 223 4 m. m. NOUN admet-144 223 5 chiba chiba PROPN admet-144 223 6 , , PUNCT admet-144 223 7 y. y. PROPN admet-144 223 8 ishii ishii PROPN admet-144 223 9 and and CCONJ admet-144 223 10 y. y. PROPN admet-144 223 11 sugiyama sugiyama PROPN admet-144 223 12 , , PUNCT admet-144 223 13 aaps aap NOUN admet-144 223 14 journal journal VERB admet-144 223 15 11 11 NUM admet-144 223 16 ( ( PUNCT admet-144 223 17 2009 2009 NUM admet-144 223 18 ) ) PUNCT admet-144 223 19 262 262 NUM admet-144 223 20 - - SYM admet-144 223 21 276 276 NUM admet-144 223 22 . . PUNCT admet-144 224 1 [ [ X admet-144 224 2 10 10 NUM admet-144 224 3 ] ] X admet-144 224 4 d. d. PROPN admet-144 224 5 hallifax hallifax PROPN admet-144 224 6 , , PUNCT admet-144 224 7 h. h. PROPN admet-144 224 8 rawden rawden PROPN admet-144 224 9 , , PUNCT admet-144 224 10 n. n. PROPN admet-144 224 11 hakooz hakooz PROPN admet-144 224 12 and and CCONJ admet-144 224 13 j. j. PROPN admet-144 224 14 houston houston PROPN admet-144 224 15 , , PUNCT admet-144 224 16 drug drug NOUN admet-144 224 17 metabolism metabolism NOUN admet-144 224 18 and and CCONJ admet-144 224 19 disposition disposition NOUN admet-144 224 20 33 33 NUM admet-144 224 21 ( ( PUNCT admet-144 224 22 2005 2005 NUM admet-144 224 23 ) ) PUNCT admet-144 224 24 1852 1852 NUM admet-144 224 25 - - SYM admet-144 224 26 1858 1858 NUM admet-144 224 27 . . PUNCT admet-144 225 1 [ [ X admet-144 225 2 11 11 NUM admet-144 225 3 ] ] X admet-144 225 4 y. y. PROPN admet-144 225 5 shitara shitara PROPN admet-144 225 6 , , PUNCT admet-144 225 7 k. k. PROPN admet-144 225 8 maeda maeda PROPN admet-144 225 9 , , PUNCT admet-144 225 10 k. k. PROPN admet-144 225 11 ikejiri ikejiri PROPN admet-144 225 12 , , PUNCT admet-144 225 13 k. k. PROPN admet-144 225 14 yoshida yoshida PROPN admet-144 225 15 , , PUNCT admet-144 225 16 t. t. PROPN admet-144 225 17 horie horie PROPN admet-144 225 18 and and CCONJ admet-144 225 19 y. y. PROPN admet-144 225 20 sugiyama sugiyama PROPN admet-144 225 21 , , PUNCT admet-144 225 22 biopharmaceutics biopharmaceutics PROPN admet-144 225 23 & & CCONJ admet-144 225 24 drug drug PROPN admet-144 225 25 disposition disposition NOUN admet-144 225 26 34 34 NUM admet-144 225 27 ( ( PUNCT admet-144 225 28 2013 2013 NUM admet-144 225 29 ) ) PUNCT admet-144 225 30 45 45 NUM admet-144 225 31 - - SYM admet-144 225 32 78 78 NUM admet-144 225 33 . . PUNCT admet-144 226 1 Β© Β© X admet-144 226 2 2015 2015 NUM admet-144 226 3 by by ADP admet-144 226 4 the the DET admet-144 226 5 authors author NOUN admet-144 226 6 ; ; PUNCT admet-144 226 7 licensee licensee PROPN admet-144 226 8 iapc iapc PROPN admet-144 226 9 , , PUNCT admet-144 226 10 zagreb zagreb PROPN admet-144 226 11 , , PUNCT admet-144 226 12 croatia croatia PROPN admet-144 226 13 . . PUNCT admet-144 227 1 this this DET admet-144 227 2 article article NOUN admet-144 227 3 is be AUX admet-144 227 4 an an DET admet-144 227 5 open open ADJ admet-144 227 6 - - PUNCT admet-144 227 7 access access NOUN admet-144 227 8 article article NOUN admet-144 227 9 distributed distribute VERB admet-144 227 10 under under ADP admet-144 227 11 the the DET admet-144 227 12 terms term NOUN admet-144 227 13 and and CCONJ admet-144 227 14 conditions condition NOUN admet-144 227 15 of of ADP admet-144 227 16 the the DET admet-144 227 17 creative creative ADJ admet-144 227 18 commons common NOUN admet-144 227 19 attribution attribution NOUN admet-144 227 20 license license NOUN admet-144 227 21 ( ( PUNCT admet-144 227 22 http://creativecommons.org/licenses/by/3.0/ http://creativecommons.org/licenses/by/3.0/ PROPN admet-144 227 23 ) ) PUNCT admet-144 227 24 http://creativecommons.org/licenses/by/3.0/ http://creativecommons.org/licenses/by/3.0/ PROPN