Upsala J Med Sci 100: 41-46, 1995 Torsten Teorell, the Father of Pharmacokinetics Lennart K. Paalzow Department of Biopharmaceutics & Pharmacokinetics, Uppsala University, Box 580, S- 751 23 Uppsala, Sweden During t h e summer o f 1937 T o r s t e n T e o r e l l s u b m i t t e d two s c i e n t i f i c p a p e r s (1,2) f o r p u b l i c a t i o n which a p p e a r e d i n A r c h i v e s I n t e r n a t i o n a l e s e t Pharmacodynamie e t de T h e r a p i e i n October i n t h e s a m e y e a r . More t h a n 30 years l a t e r t h e s e two a r t i c l e s came t o be c o n s i d e r e d a s two of t h e most i m p o r t a n t c o n t r i b u t i o n s t o drug r e s e a r c h and l e d t o T e o r e l l b e i n g c h a r a c t e r i z e d a s t h e f a t h e r of p h a r m a c o k i n e t i c s . Both t h e s e p a p e r s had t h e same t i t l e , " K i n e t i c s of d i s t r i b u t i o n of s u b s t a n c e s a d m i n i s t e r e d t o t h e body", and t h e f i r s t one d e a l t w i t h e x t r a v a s c u l a r modes of a d m i n i s t r a t i o n (l), w h i l e t h e second one d i s c u s s e d t h e i n t r a v a s c u l a r modes ( 2 ) . I n t h e i n t r o d u c t i o n t o t h e f i r s t p a p e r T e o r e l l p o i n t e d o u t t h a t a t t h a t t i m e t h e i n t e r e s t of t h e p h y s i c i a n o r t h e p h y s i o l o g i s t was f o c u s e d more on p r a c t i c a l p o i n t s such a s t e s t i n g t h e p r o p e r dosage o r s u i t a b l e ways of a d m i n i s t r a t i o n , o r on t h e f i n e r mechanism i n v o l v e d i n t h e e f f e c t s produced by t h e drug, whereas v e r y l i t t l e work seemed t o have been devoted t o . t h e k i n e t i c s , i . e . t h e t i m e r e l a t i o n s o f drug a c t i o n . The o b j e c t i v e s of t h e two p a p e r s by T e o r e l l were t o d e r i v e " g e n e r a l mathematical r e l a t i o n s from which it i s p o s s i b l e , a t l e a s t f o r p r a c t i c a l p u r p o s e s , t o d e s c r i b e t h e k i n e t i c s of d i s t r i b u t i o n of s u b s t a n c e s i n t h e body" and t o p r e s e n t t i m e - c o n c e n t r a t i o n c u r v e s a s i l l u s t r a t i o n s of t h e r e l a t i o n s d e r i v e d . To d e s c r i b e what happens t o a drug i n t h e body when it i s a d m i n i s t e r e d by an e x t r a v a s c u l a r mode, e . g . by t h e subcutaneous r o u t e , T e o r e l l made a s i m p l i f i e d model of t h e body a s i l l u s t r a t e d i n F i g . 1. Blood i s c i r c u l a t e d t h r o u g h o u t t h e body and can be i l l u s t r a t e d 41 by a c i r c l e of a s water p i p e l i n e i n c o n t a c t w i t h t h e t i s s u e s of t h e body. Each t i s s u e h a s a c e r t a i n volume, and as s e e n i n t h e f i g u r e a drug i s t r a n s p o r t e d by d i f f u s i o n from t h e subcutaneous t i s s u e t o t h e blood ( a b s o r p t i o n p r o c e s s w i t h t h e r a t e c o n s t a n t k, ) and t h e n c i r c u l a t e d throughout t h e body. The p r o c e s s e s of t r a n s p o r t from t h e blood t o t h e d i f f e r e n t t i s s u e s a r e d e s c r i b e d by t h e r a t e c o n s t a n t i n t o t h e t i s s u e and by a n o t h e r r a t e c o n s t a n t o u t of i t . Some o r g a n s , such a s t h e l i v e r and t h e kidney, have t h e c a p a c i t y t o e l i m i n a t e t h e drug and t h e y a r e i l l u s t r a t e d by one r a t e c o n s t a n t o u t from t h e blood ( F i g . 1 ) . F i g . 1. From T o r s t e n T e o r e l l r e f . 1. T e o r e l l t h e n d e r i v e d t h e d i f f e r e n t i a l e q u a t i o n s f o r t h e s e p r o c e s s e s and p r e s e n t e d t h e i r s o l u t i o n s . B y g i v i n g t h e r a t e c o n s t a n t s and volumes c e r t a i n p o s s i b l e v a l u e s , he c a l c u l a t e d t h e t i m e c o u r s e of drug amounts i n t h e body, e x p r e s s e d a s p e r c e n t of t h e dose, a s i l l u s t r a t e d i n F i g . 2 . A s s e e n i n t h i s f i g u r e , t h e r a p i d a b s o r p t i o n a f t e r a subcutaneous dose produces a peak c o n c e n t r a t i o n i n t h e b l o o d 42 t h a t d e c l i n e s e x p o n e n t i a l l y o v e r t i m e , w h i l e t h e c o n c e n t r a t i o n i n t h e t i s s u e , which most p r o b a b l y i n c l u d e s t h e s i t e of a c t i o n , p e a k s l a t e r t h a n t h a t i n t h e b l o o d b u t t h e n d e c l i n e s i n p a r a l l e l w i t h t h e c o n c e n t r a t i o n i n t h e b l o o d . T h e e l i m i n a t i o n c u r v e and t h e amount of d r u g i n t h e s u b c u t a n e o u s d e p o t a r e a l s o i l l u s t r a t e d i n F i g . 2 . F I G . 3 Typical Case of Extravascular Adtrii- ttistratiotr in the absence of tissue in- activation. (k, = 0.2; k2 = 0.01; k, = 0.005; i.e. " blood " volume/" tissue " volume is I : 2; k, = 0 . 0 0 5 ; k, = 0 ) . F i g . 2 . From T o r s t e n T e o r e l l r e f . 1. F u r t h e r m o r e , by p e r f o r m i n g s e v e r a l n u m e r i c a l c a l c u l a t i o n s , T e o r e l l emphasized t h a t a marked change i n t h e a b s o r p t i o n 43 p r o p e r t i e s may b r i n g a b o u t a marked change i n t h e m a g n i t u d e and d u r a t i o n o f t h e b l o o d and t i s s u e c o n c e n t r a t i o n c u r v e s , a n d s t a t e s t h a t " t h e s e and o t h e r c o n c l u s i o n s may have b e a r i n g s upon p r a c t i c a l pharmacology and t h e r a p e u t i c s " . These c o n c l u s i o n s may t o d a y seem s e l f - e v i d e n t , b u t o n e h a s t o r e c a l l t h a t a t t h a t t i m e nobody had r e a l l y t h o u g h t t h a t w e c o u l d t r e a t t h e d i s t r i b u t i o n o f d r u g s i n t h e body i n s u c h a s i m p l i s t i c a n d c l e a r way. A l l t h e c o n c l u s i o n s p r e s e n t e d by T e o r e l l a r e c e r t a i n l y s t i l l v a l i d and a t t h a t t i m e t h e y s h o u l d h a v e been a n e y e - o p e n e r t o t h o s e who w e r e u s i n g d r u g s b u t who c l e a r l y w e r e unaware o f what c a n happen t o a d r u g i n t h e body. However, t h e s e t w o p a p e r s of T e o r e l l p r o d u c e d t h e o p p o s i t e e f f e c t and t h e r e v i e w e r s o f t h e a p p l i c a t i o n s f o r t h e c h a i r i n p h y s i o l o g y , which T e o r e l l o b t a i n e d i n 1 9 4 0 , r a t h e r c o n s i d e r e d t h e s e two p a p e r s more a s a b u r d e n t h a n a m e r i t . C o n s e q u e n t l y , t h e y w e r e f o r g o t t e n a n d n o t h i n g r e a l l y happened f o r more t h a n 2 5 y e a r s , when German a n d e s p e c i a l l y U.S. s c i e n t i s t s r e d i s c o v e r e d T e o r e l l ' s work. The word p h a r m a c o k i n e t i c s was i n t r o d u c e d by t h e German p r o f e s s o r F . H . Dost i n 1953 a n d i n a r e v i e w a r t i c l e ( 3 ) by John G . Wagner ( 1 9 8 1 ) on t h e h i s t o r y o f p h a r m a c o k i n e t i c s w e c a n read t h e f o l l o w i n g : " I n 1937, T e o r e l l , a Swedish p h y s i o l o g i s t a n d b i o p h y s i c i s t , p u b l i s h e d two r e m a r k a b l e a r t i c l e s which many now a t t r i b u t e a s b e i n g t h e f o u n d a t i o n s of modern p h a r m a c o k i n e t i c s " . Thanks t o t h e work o f v a r i o u s g r o u p s , f o r example S i d n e y Riegelman, B e r n a r d B . B r o d i e , E i n o N e l s o n , G e r h a r d Levy, John Wagner a n d o t h e r s i n t h e U.S.A., and by Europeans s u c h a s Ekkehard Xruger-Thiemer, E . J . A r i e n s a n d J a c q u e s v a n Rossum, p h a r m a c o k i n e t i c s q u i c k l y d e v e l o p e d d u r i n g t h e 1 9 6 0 ' s . One i m p o r t a n t c o n t r i b u t o r y f a c t o r was t h e r a p i d a d v a n c e s i n b i o a n a l y t i c a l t e c h n i q u e s , which made it p o s s i b l e t o a n a l y s e m i n u t e d r u g c o n c e n t r a t i o n s i n plasma, u r i n e and o t h e r t i s s u e s . D u r i n g t h i s p e r i o d t h e s o - c a l l e d c o m p a r t m e n t a l models were u s e d f o r t h e m a t h e m a t i c a l i n t e r p r e t a t i o n o f d a t a . The main drawback o f t h i s a p p r o a c h w a s a p p a r e n t a t l e a s t t o t h o s e who were g o i n g t o u t i l i z e t h e f i n d i n g s , i . e . t h e p h y s i c a n s , who h a d d i f f i c u l t i e s i n u n d e r s t a n d i n g t h e meaning o f t h e i n f o r m a t i o n p r o d u c e d . 44 I n t h e b e g i n n i n g of t h e 1 9 7 0 ' s a new e r a of p h a r m a c o k i n e t i c s began when t h e r e s e a r c h became more o r i e n t e d towards a p h y s i o l o g i c a l approach. With t h e i n t r o d u c t i o n of t h e c l e a r a n c e concept by Rowland e t a l . ( 1 9 7 3 ) , a b e t t e r u n d e r s t a n d i n g of p h y s i o l o g i c a l f a c t o r s s u c h a s blood flow, h e p a t i c m e t a b o l i c c a p a c i t y and plasma p r o t e i n b i n d i n g was a c h i e v e d ( 4 ) . During a b o u t t h e same time p e r i o d , a n o t h e r t y p e of p h a r m a c o k i n e t i c model appeared i n t h e l i t e r a t u r e . B i s c h o f f and Dedrick ( 1 9 6 8 ) d e s c r i b e d what t h e y c a l l e d a p h y s i o l o g i c a l flow model, which t o o k i n t o account t h e i n f l u e n c e of t h e blood flow and b i n d i n g o f d r u g s i n d i f f e r e n t t i s s u e s of t h e body ( 5 ) . The e l e g a n t t h i n g about t h e s e models was t h a t it was p o s s i b l e t o s c a l e them up from a n i m a l s t o humans by changing, f o r example, t h e magnitude of animal t i s s u e blood flows and t h e e l i m i n a t i o n c a p a c i t y t o t h a t found i n m a n . By t h i s way t h e human s i t u a t i o n c o u l d be p r e d i c t e d from t h e outcome of a n a n i m a l e x p e r i m e n t . Once a g a i n T o r s t e n T e o r e l l ' s work was r e d i s c o v e r e d , s i n c e it was obvious t h a t t h e model T e o r e l l had used w a s a l s o t h e f i r s t p h y s i o l o g i c a l model, and i n h i s honour a c o n f e r e n c e was a r r a n g e d i n 1 9 7 2 a t t h e F o g e r t y I n t e r n a t i o n a l C e n t e r a t N I H i n Bethesda, which he a t t e n d e d and where h i s achievements were r e c o g n i z e d ( 6 ) . During t h e l a s t two decades p h a r m a c o k i n e t i c s h a s advanced e x p l o s i v e l y and t o d a y it i s one of t h e most q u i c k l y d e v e l o p i n g b r a n c h e s of s c i e n c e , e s p e c i a l l y of t h e p h a r m a c e u t i c a l s c i e n c e s , and it p r o v i d e s u s w i t h a fundamental knowledge upon which modern d r u g t h e r a p y r e s t s . P e r s o n a l l y , I know t h a t T e o r e l l was p l e a s e d w i t h t h e f a c t t h a t Uppsala U n i v e r s i t y became t h e f i r s t u n i v e r s i t y i n t h e Nordic c o u n t r i e s t h a t e s t a b l i s h e d a c h a i r i n p h a r m a c o k i n e t i c s . I t h a s always been a p r i v i l e g e and an honour f o r m e t o h o l d t h i s p o s i t i o n a t a u n i v e r s i t y t h a t i s known a l l o v e r t h e world a s t h e p l a c e a t which T o r s t e n T e o r e l l , t h e f a t h e r o f p h a r m a c o k i n e t i c s , was working. There i s no r i s k t h a t h i s name w i l l be f o r g o t t e n . 45 R e f e r e n c e s . 1. Teorell, T.: Kinetics of distribution of substances administered to the body. I. The extravascular modes of administration. Arch Int Pharmacodyn et Ther 57: 205-225, 1937. 2. Teorell, T.: Kinetics of distribution of substances administered to the body. 11. The intravascular modes of administration. Arch Int Pharmacodyn et Ther 57: 226-240, 1937. 3. Wagner, J.G.: History of pharmacokinetics. Pharmacol Ther 12: 537-562, 1981. 4. Rowland, M., Benet, L.Z. & Graham, C . G . : Clearance concepts in pharmacokinetics. J Pharmacokin Biopharm 1: 123-136, 1973. 5. Bischoff, K.B. & Dedrick, R.L.: Thiopental pharmacokinetics. J Pharm Sci 57: 1347-1357, 1968. 6. Teorell, T., Dedrick, R.L. & Condliffe, P . E . : Pharmacology and Pharmacokinetics, Fogerty International Center Proceedings No 20, Plenum, New York, 1974. 46