







































Refractory Epilepsy: Mechanisms 
of Pharmacoresistance 

Ariel Le, Makenzie Thomas, Brady Stallman, Kathryn 
Meadows, Vidya Bhargava

Volume One 
Edition One 
February 2021 

GEORGETOWN SCIENTIFIC
RESEARCH JOURNAL

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https://doi.org/10.48091/UWYG8998 

Refractory Epilepsy: Mechanisms of 
Pharmacoresistance  

Ariel Le, Makenzie Thomas, Brady Stallman, Kathryn Meadows, and Vidya Bhargava 

Department of Human Science, Georgetown University School of Nursing and Health Studies, 
Washington D.C., United States of America 

E-mail: aql3@georgetown.edu, mst82@georgetown.edu, bes104@georgetown.edu,
kgm65@georgetown.edu, vdb29@georgetown.edu

Abstract 
Refractory or drug-resistant epilepsy is a complex and debilitating disorder that impacts over one-

third of people diagnosed with epilepsy. Many studies have suggested a variety of possible hypotheses for 
drug-resistant epilepsy, including the degeneration of neural networks, alterations of anti-epileptic drug 
(AED) targets, intrinsic severity/frequency of seizures, and genetic predisposition to pharmacoresistance. 
However, extensive research suggests that the overexpression of efflux protein transporters in brain tissue 
is the most viable hypothesis. Specifically, the overexpression of P-glycoproteins (P-gps) at the blood brain 
barrier proves the most compelling mechanism to discuss further. Studying the mechanisms of these 
transporters provides critical insight for new ways to combat pharmacoresistance. Thus, this review 
evaluates the co-administration of P-gp inhibitors with AEDs as a promising, yet relatively unexplored, 
treatment option for refractory epilepsy. This review specifically considers Tariquidar (TQD) the most 
promising P-gp inhibitor for refractory epilepsy treatment. This work aims to evaluate the role of P-
gp overexpression in refractory epilepsy, consolidate current research about potential treatment options, 
and identify discrepancies or gaps in the literature related to P-gp inhibitory treatments for refractory 
epilepsy. It was concluded that, as a result of increased drug efflux processes at the blood brain barrier, 
overexpression of P-gp is the leading cause of pharmacoresistance. By inhibiting the activity of 
these proteins with the drug Tariquidar, an effective treatment for refractory epilepsy may become a 
reality. 

Keywords: refractory epilepsy, pharmacoresistance, overexpression, P-glycoprotein, Tariquidar 

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1. Introduction
Epilepsy is a chronic neurological disorder

characterized by spontaneous, repeated, and 
unprovoked seizures resulting from abnormal 
electrical connections between neurons in the 
brain.1 Characterized by spontaneous electrical 
disturbances in the brain, these seizures often 
result in physical manifestations such as 
convulsion, loss of consciousness, sensory 
disturbances, or uncontrolled 
movements.2 Epilepsy encompasses many 
different types of seizure disorders that are 
classified according to relative regions of brain 
dysfunction, types of seizures present, and varying 
degrees of causal explanation. Clinical diagnosis of 
epilepsy requires at least two isolated seizures 
unrelated to brain injury, drug usage, metabolic 
disorders, or acute systemic dysfunction.3  
 Impacting 2.2 million people in the United 
States and over 65 million people worldwide, 
epilepsy is the most common neurological disorder 
in the world. It accounts for 0.5% of the global 
burden of disease, a measure that considers the 
number of years of life lost to premature death, 
illness, and disability. While this condition is 
prevalent across all age demographics, it 
disproportionately affects individuals in early 
childhood or late adulthood.3 People with epilepsy 
are up to three times more likely to experience 
premature death compared to the general 
population. 1 in every 1,000 adults with epilepsy 
suffer from sudden unexpected death in epilepsy 
(SUDEP) every year, and those with drug-
resistant forms are at increased risk of SUDEP. In 
the United States alone, over 150,000 new cases of 
epilepsy are diagnosed annually and one in 26 
individuals are projected to develop epilepsy over 
the course of their lifetimes. Direct annual medical 
care costs of epilepsy in the United States total 
$9.6 billion and contribute significant financial 
burden to sufferers.3 Along with the difficulties 
associated with seizures and other related 
symptoms, people living with epilepsy are often 

faced with challenges accessing high-quality 
healthcare, navigating treatment options, and 
dealing with public misunderstanding of the 
disease. In many areas across the globe, people 
with epilepsy also experience reduced access to 
educational and vocational opportunities as a result 
of stigma and discrimination associated with the 
disease.2 This emphasizes the need to find 
treatments or cures for epilepsy. In doing so, the 
detrimental impacts of the condition and the 
socioeconomic disparities associated with it may be 
relieved.  

While there are numerous therapeutic 
options available to treat epilepsy—such as 
antiepileptic drugs (AEDs), surgical intervention, 
nerve stimulation, or specialized diets—treatment 
methods are often ineffective. Over one-third of 
people diagnosed with epilepsy will develop 
refractory (drug-resistant) epilepsy as a result 
of pharmacoresistance, the inability to control 
seizure activity through AED therapy.4 This form 
of epilepsy is clinically diagnosed after two trials of 
AEDs fail to manage or cease seizure activity. 
While about 50% of newly diagnosed epileptic 
patients obtain full seizure control within the first 
AED treatment and 13% after switching to a 
second AED treatment, 20-25% of total patients 
still do not see improvement after a single AED or 
a combination of AEDs.5 Management of 
refractory epilepsy is particularly challenging 
because there is little conclusive evidence about the 
causes or mechanisms of pharmacoresistance, and 
individualized treatment plans are necessary due to 
different underlying disease mechanisms.6 Some 
possible causes for drug-resistance may include 
environmental factors, including trauma and prior 
drug exposure, or genetic predispositions that 
impact the degree of absorption, metabolism, and 
uptake of AEDs at the blood brain barrier.  

Most of the current research on the 
mechanisms of refractory epilepsy suggests that 
drug-resistance in epilepsy is caused by increased 
activity and expression of multidrug efflux 
transporter proteins in the ATP-binding cassette 
(ABC) protein transporter family.7 There are three 
major types of ABC transporters that play a 

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significant role in the failure of AEDs to control 
refractory epilepsy seizures: permeability-
glycoproteins (p-glycoproteins or P-gps), 
multidrug resistant-associated proteins (MRPs), 
or breast cancer resistant proteins (BCRPs).7 
These active transporters use the energy of ATP 
through ATP hydrolysis to allow for the 
movement of molecules across a membrane, 
although ABC transporters specifically use an 
alternate access mechanism, which entails 
switching between “inward- and outward-facing
states” at the membrane which, in turn, alternates 
whether the ligand-binding site is exposed inside 
or outside the membrane.8 Many studies suggest 
this group of ABC transporters and their related 
efflux mechanisms to be the major cause 
of pharmacoresistance in refractory epilepsy, and 
the most compelling evidence suggests that the 
overexpression, or increased expression, of P-
glycoprotein transporters most significantly 
reduces uptake of AEDs at the blood brain 
barrier.7,9 Additional studies have shown that the 
inhibition of these particular P-gp transporters can 
reduce efflux transporter mechanisms and, 
subsequently, can potentially�eliminate 
pharmacoresistance altogether.  
� � *O� essence, the overexpression of P-
glycoproteins in the brain leading to the reduced 
uptake of AEDs at the blood brain barrier is the 
most promising target for the treatment of 
refractory epilepsy.  
2.� The Transporter Hypothesis in Refractory�
Epilepsy
 Many studies have worked to evaluate various 
theories regarding the potential mechanisms 
of pharmacoresistance in refractory epilepsy, 
although there is a general consensus that protein 
transporters have the most influence over 
refractoriness. This is especially noted in a 
comprehensive review focused on drug-resistant 
epilepsy that evaluated a wide variety of studies on 
refractory epilepsy and summarized the potential 
hypotheses for mechanisms of 
pharmacoresistance.9 Tang et al., 2017 suggested 
that the drug-resistance of refractory epilepsy may 
come from seizure-induced neural damage that 

prevents anti-epilepsy drugs from accessing their 
neuronal targets. Another collection of studies 
included in the same review suggested 
that pharmacoresistance is inherent to the severity 
of epilepsy.8 While many of these hypotheses are 
biologically plausible, there is a significant lack of 
evidence, association, consistency, and specificity 
in the literature to demonstrate their validity. 

However, one hypothesis from the review 
stood out as the most promising mechanism for 
refractory epilepsy: the transporter hypothesis. 
The transporter hypothesis suggests that the 
overexpression of efflux transporter proteins in the 
brain tissue of epileptic patients causes drug 
resistance by decreasing the permeability of the 
blood brain barrier for AEDs.10 There 
are different types of protein transporters that 
carry out this mechanism of 
pharmacoresistance: P-gps, MRPs, and BRCs, 
which are all part of the ABC transporter 
family.7,9 Out of these transporters, the 
overexpression of P-gp is most prominently 
associated with pharmacoresistance, as increased 
expression of P-gp in the brain tissue of refractory 
epilepsy patients had a low AED response.9 The 
overexpression of MRPs shows similar promise as 
a potential mechanism of refractory epilepsy, but 
they have not been extensively studied with 
controls to further prove their association. While 
BCRPs perform a similar role 
in pharmacoresistance, it has been suggested that 
these transporters have better therapeutic potential 
for cancer rather than refractory 
epilepsy.9 Ultimately, based on the current 
findings and evidence, it can be deduced that the 
clearance of AEDs by P-gps shows the most 
promise as a mechanism of refractory epilepsy. 
Thus, resources should be allocated towards 
exploring these proteins and investigating them as 
a target for future treatment.   

An earlier review from 2011, which 
elaborated on each type of transporter and their 
mechanisms at the BBB, detailed the inhibition of 
P-gp expression as a potential treatment
option.10 To build upon these analyses, this review
focuses on P-gp overexpression, its role in

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refractory epilepsy, and potential treatments that 
target these mechanisms.  
3. The Overexpression and Mechanisms of P-
glycoproteins in Refractory Epilepsy

As previously mentioned, current data 
shows that about one-third of epilepsy patients do 
not respond to most types of AEDs, and it has 
been hypothesized in recent years that one 
potential mechanism for the resistance to AEDs is 
the overexpression of P-gp in the blood-brain 
barrier (BBB).11 As ABC transporters, P-gps use 
ATP hydrolysis to allow for efflux of molecules 
using the aforementioned alternate access 
mechanism.8,12 More specifically, P-gps are 
exporters, so they actively work towards moving 
molecules outside of the cell rather than inside, so 
it is clear that the overexpression of these exporters 
are bound to lead to decreased AED 
concentration.8 

These protein transporters can exist in 
large numbers in a variety of locations in the body 
such as the intestines, liver, kidneys, and the BBB. 
The protein is likely expressed in these organs to 
serve as a defense mechanism against foreign 
substances.12,13 For example, this protein exists in 
the intestinal epithelium, where it pumps toxins 
back into the intestinal lumen. P-gps can play an 
integral role in the effluxion, or clearance, of 
chronic disease drugs. Specifically, P-gp is a key 
efflux protein of the BBB that actively transports 
large amounts of lipophilic drugs, including 
AEDs, out of the BBB membrane and back into 
the bloodstream, therefore resulting 
in pharmacoresistance to therapeutic medications 
intended to target the brain.11,12  

There have been many clinical studies that 
demonstrated how the decreased concentration of 
AEDs can result from P-gp overexpression. In one 
case study, surgery was conducted on a patient with 
partial refractory epilepsy to alleviate epileptic 
symptoms. Prior to this study, the patient was 
treated with many different AEDs and doses with 
no measured success in controlling the patient s
symptoms.5 Prior to surgery, researchers collected 
and measured AED blood levels in the patient's 
serum samples for 25 days before each 

administered dose of AEDs to observe the 
patient s AED concentration in the blood. It was
found that all types of the AEDs that the patient 
received were observed in subtherapeutic levels in 
a significant portion of the serum samples 
collected. This indicates very low AED 
concentration throughout the blood. During the 
surgery, some samples of brain tissue were 
collected for immunohistochemical analysis to 
determine the cause of these subtherapeutic AED 
levels in the blood. From this analysis, it was found 
that the patient had high brain expression of P-
gps in not only endothelial cells of the BBB but 
also in astrocytes and neurons. This overexpression 
of P-gps in regions where drug elimination 
actively takes place suggests that the protein plays 
an integral role in the efflux and clearance of 
AEDs from the brain. 5 This study is consistent 
with other case studies on patients with refractory 
epilepsy.  

 In a rat model of epilepsy, P-
gp overexpression was assessed following the 
administration of an anti-seizure medication, 
phenobarbital. Immunohistochemical analysis 
showed a striking overexpression of P-gp in the 
limbic brain regions of the rats that did not 
respond to the medication.13 In particular, 
overexpression of P-gp could be narrowed down to 
the brain capillary endothelial cells of the 
BBB.13 These findings were consistent with the 
case study mentioned above, suggesting an 
association between P-gp overexpression and 
AED response. Other studies on BCRPs and 
MRPs have not been able to fully conclude these 
same associations with the AED 
response, suggesting that P-gps are the most 
promising candidates for a therapeutic approach.  

Other experiments focused on looking at 
the specific mechanism of P-gps with specific 
substrates. For example, one study conducted the 
brain-to-plasma difference of 10-OHCBZ, an 
active metabolite, in refractory epilepsy patients 
who did not respond to the AED treatment 
Oxcarbazepine.14 In this study, surgery was 
conducted to alleviate the epileptic condition of 
the patients, during which researchers 
intraoperatively measured 10-OHCBZ levels to 

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determine if it is a substrate of P-gp and to 
understand the relationship between its brain-to-
plasma concentration ratio and the levels of 
expression of P-gp. The results showed that 10-
OHCBZ acts as a substrate for P-gp, and the 
concentration of 10-OHCBZ in the brain was not 
correlated to the plasma levels of the patients. 
However, a significant inverse linear relationship 
was found between the levels of expression of P-
gp and the brain-to-plasma concentration ratio of 
10-OHCBZ.14 This inverse relationship showed
that higher levels of P-gp resulted in lower levels
of the active metabolite past the BBB, providing
evidence of the hypothesized P-gp mechanisms.
The conclusions of 10-OHCBZ apply to AEDs
because the data showed that higher expressions of
P-gp lead to lower expressions of 10-OHCBZ,�
and intracellular levels of the metabolite were�
increased when XR9576, a P-gp inhibitor, was�
introduced. However, these conclusions are not�
necessarily reliable due to the lack of control brain�
tissue from drug-responding patients.�
Furthermore, in-vitro studies do not necessarily�
confirm or reflect these mechanisms as would in-
vivo models for refractory epilepsy.13 The�
observational nature of the previous study is useful�
in developing a base for understanding the�
functions of P-gp and developing hypotheses, but�
in-vivo studies are needed to test and prove these�
hypotheses. Nevertheless, this pilot study still�
provided some fundamental insight into the�
mechanisms of P-gp overexpression�
in pharmacoresistance and demonstrated how�
substrates of P-gp, including AEDs, have�
difficulty crossing the BBB and reaching the brain�
if there is an overexpression of these transporters.

An in-vivo study by Van Vliet et al.
measured the levels of phenytoin (PHT), a
common AED used to control seizures, in
different brain regions of both epileptic and
nonepileptic rats.15 The researchers wanted to
compare PHT levels in regions of the brain with
an overexpression of P-gp, such as
the parahippocampal cortex and the temporal
hippocampus, to PHT levels in brain regions with
lower P-gp expression. The concentration of PHT
in regions with overexpression of P-gp was

significantly reduced compared to regions with 
lower P-gp expression. These results were, once 
again, consistent with the earlier findings, 
demonstrating the relationship between increased 
P-gp expression and decreased levels of AED in
the brain.15 Overall, it has been established,
through studies using different AED substrates
and refractory epilepsy models, that the
overexpression of P-gp efflux transporters leads to
decreased concentration of AEDs in the brain and,
consequently, pharmacoresistance. Some of these
studies have also suggested this mechanism as a
potential therapeutic target, specifically with the
use of P-gp inhibitors.15,16 Together, the findings
of these past works suggest promising research
implications for P-gps as future treatment targets,
which will be discussed in the next section.
4. Improving Standard of Care for Refractory
Epilepsy
4.1 Significance of P-gp Inhibitors in Reducing 
Pharmacoresistance  

Although overexpression of P-gps has 
been identified as a highly probable mechanism of 
drug resistance in epilepsy, treatment methods 
have yet to significantly account for this new 
knowledge. A promising yet relatively unexplored 
treatment option lies in therapeutics that target the 
activity of P-gps. P-gp inhibitors are a specialized 
class of substances that block or bypass the efflux 
activity of P-gps at the BBB.16 In regards to AEDs 
specifically, these inhibitors work to prevent the 
efflux of AEDs from endothelial cells of the blood 
brain barrier (Figure 1), thus allowing for 
increased therapeutic effect. These inhibitors 
function to either block P-gp binding sites, reduce 
ATP hydrolysis by P-gp, or weaken cell membrane 
lipids.16 The previously mentioned in-vitro study 
using 10-OHCBZ to observe the effect of P-
gps on intracellular drug concentration briefly 
introduced the use of P-gp inhibitors, which 
resulted in increased intracellular drug 
concentration.14 This previous work was able to 
provide the fundamental insight needed to suggest 
that concurrent administration of AED substrates 
with P-gp inhibitors may increase drug 

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bioavailability or uptake at the BBB and result in 
an improved therapeutic effect.14,16   

Figure 1. P-gp Inhibition to Prevent AED Efflux at the Blood Brain Barrier 1

Table 1. Classification and Limitations of P-g Inhibitors 

Generation Specificit
y 

Limitations Advantages Examples 

First 
Generation

Low -High toxicity
-Must be administered in low
doses 
-High serum concentrations
-Wide range of substrate 
capabilities 

-Most pharmacologically
active 
-Significant research 
accomplished 

Verapamil 

Second 
Generation

Medium -Inhibitory effect of unintended
enzymes and other ABC 
transporters 

-Greater affinity of P-gp Valspodar 

Third 
Generation

High -Many still in developmental
stage/not ready for clinical use 

-Low toxicity
-Can target specific 
locations 

Tariquidar 

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Three distinct generations of P-
gp inhibitors that perform similar functions have 
been identified (Table 1). First-generation 
inhibitors are substances originally developed to 
treat other conditions that were found to also 
successfully inhibit P-gps. First generation 
inhibitors are the most pharmacologically active, 
but they pose potential limitations in dosage due 
to their latent toxicity, unusually high serum 
concentrations, and ability to substrate with a wide 
range of unintended, biologically beneficial 
transporters and enzymes.16 Second-generation 
inhibitors do not hold the same range of 
pharmacological ability as the first-generation, but 
they do possess a greater affinity for P-gps, 
allowing for more specific targeting in the body. 
However, second-generation inhibitors are limited 
in clinical use by their tendency to inhibit certain 
enzymatic activities and other ABC transporters 
that lead to complicated drug-drug 
interactions.16  Most third-generation inhibitors 
are still in the clinical development phase and aim 
to act with high P-gp specificity and low toxicity. 
While all three generations of P-gp inhibitors face 
potential restrictions in their use, they also offer 
promising properties as a clinical treatment for 
refractory epilepsy.   
4.2 Tariquidar as a Promising Therapeutic Option 

In identifying P-gp inhibition as a 
potential therapeutic option for refractory epilepsy, 
it is important to consider the specific functions 
and locations of these inhibitors. P-gp inhibitors 
may specifically target overexpression in the 
intestines, liver, brain, and kidneys or may only 
play a pharmacological role in increasing the 
uptake of certain drugs.17 Two such P-
gp inhibitors, Tariquidar (TQD) and Verapamil, 
have been identified as potential treatments for 
refractory epilepsy due to their high specificity in 
targeting the blood brain barrier.  

Many studies have provided evidence to 
indicate that Tariquidar, or TQD, is a promising 
selective inhibitor of P-gp that may offer a solution 
to refractory epilepsy. As previously tested by Van 

Vliet, E. A. et al., TQD shows great potential in 
counteracting pharmacoresistance of AEDs 
resulting from the overexpression of P-
gps.15 TQD is a third-generation P-gp inhibitor 
known for its high selectivity, long active period, 
and advantageous oral administration and 
bioavailability.17  Since its development, this 
exceptionally potent inhibitor has been considered 
one of the best ways to reduce the effects of P-
gp overexpression. The oral intake of drugs such as 
TQD is often the most convenient and safest route 
of drug administration and, following the 
administration of TQD specifically, has shown to 
have a relatively strong bioavailability. TQD also 
acts as a non-competitive inhibitor to reduce the 
ATP hydrolyzing activity of P-gps. This activity 
facilitates the transport of substances out of cells; 
thus, TQD inhibits such behavior that is key to 
pharmacoresistance.17 One study demonstrated 
the high potency of TQD as a P-gp inhibitor and 
discovered that the administration of one 
micromolar of TQD decreased the ATPase 
activity of P-gp by over 50%.18 While TQD has 
mainly been studied as a modulator of reversing 
multidrug resistance in cancer, current evidence 
has also identified TQD as a potential modulator 
of pharmacoresistance in epilepsy.12  

Many studies have demonstrated the 
inhibitory effect of TQD on P-gp overexpression 
that contributes to refractory epilepsy. Building 
upon their previous work measuring AED uptake 
in brain regions with P-gp overexpression, Van 
Vliet, E. A. et al. continued an investigation into 
the anticonvulsant effects of phenytoin (PHT) 
before and after administration of TQD. After co-
administering PHT and TQD to rats with 
frequent daily seizures, researchers analyzed brain-
to-plasma concentration ratio measurements of  
PHT.19 The researchers also recorded the 
frequency of seizures to determine any observable 
changes in the epileptic activity of the rats when 
treated with TQD. The results showed that, when 
combined with TQD, PHT levels in the rats 
remained within the therapeutic range in the blood 
for an additional 8 hours compared to PHT alone. 

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Additionally, overall seizure activity was reduced 
in rats treated with both drugs. In the control 
group, PHT treatment alone did not significantly 
decrease seizure activity until day 13. Conversely, 
the experimental group of PHT co-administered 
with TQD showed reduction in seizures during 
the first 3 days of treatment. This experiment 
concluded that the administration of TQD 
allowed for an increased uptake of PHT at the 
BBB, inhibiting the mechanism of P-gps in 
chronic epileptic rats and, thus, dramatically 
reducing the frequency of seizures. This analysis 
demonstrates TQD s ability to significantly reduce
P-gp activity and provides a promising approach
for improving the standard of care for refractory
epilepsy.

A second major study showed consistent 
findings on the effects of TQD in reducing P-
gp pharmacoresistance when co-administered 
with phenobarbital (PB), a drug widely used for its 
anti-epileptic effect.20 In this study, researchers 
used EEG monitoring and blood sampling to 
analyze seizure activity and drug concentration in 
plasma. The study used a rat model of temporal 
lobe epilepsy with pre-established drug-resistance 
to phenobarbital. In one trial, co-administration of 
TQD and PB completely eliminated seizure 
activity in four nonrespondent rats and reduced 
seizures by over 90% in the remaining two 
nonrespondent rats compared to only a 24% 
reduction in the control group receiving PB alone. 
In a remarkable example, one rat went from 
experiencing an extensive number of seizures per 
day before treatment to becoming completely 
seizure free with the co-administration of TQD 
and PB. This study concluded that the co-
administration of TQD with PB completely 
restored the anti-epileptic effect of the drug 
in pharmacoresistant rat models of temporal lobe 
epilepsy.19 Another comparable study conducted 
using human subjects discovered a 2.5 fold increase 
in AED uptake at the BBB when co-administered 
with TQD.21 Combined with the previous study, 
these results provide convincing evidence that the 
P-gp inhibitor, TQD, counteracts drug-resistance

in epileptic rats and could act as an effective 
treatment method to improve the standard of care 
in refractory epilepsy.   

In a single case study, a patient was 
administered Verapamil in conjunction with an 
AED proven to be a reliable treatment 
method.22 With the combination of Verapamil 
and the AED, the patient was able to double the 
time between hospitalizations for seizures, 
demonstrating a significant improvement. Even 
so, researchers determined that it was impossible 
to isolate the cause for the improvement, as it could 
have resulted from Verapamil, the viable AED, the 
placebo effect, or any combination of the three. 
Only further research in a controlled setting would 
determine if Verapamil is a reliable P-gp inhibitor 
and treatment for refractory epilepsy. Moreover, 
even if researchers could determine that Verapamil 
was the cause for improvement, they could not 
determine the mechanism by which Verapamil 
acted. With only this one major study providing 
inconclusive evidence, Verapamil lacks the support 
needed to establish its efficacy as a P-gp inhibitor 
and positions Tariquidar as the better therapeutic 
option.22 
4.3 Limitations of TQD 

While many developments have been made 
in studying refractory epilepsy, significant 
uncertainty must be accounted for to better 
understand treatment options, especially in 
relation to TQD. Although TQD shows the most 
promise as a treatment for refractory epilepsy, 
there are limitations that should be considered. 
Recent TQD studies have demonstrated 
significant adverse events. The aforementioned 
study by Van Vliet E. A. et al. reported significant 
abdominal pain in the TQD treatment group, 
resulting in a dissolution of the 
trial. While examining the potential application of 
TQD for multidrug resistance in cancer, 
research was discontinued after 41% of subjects 
reported adverse effects to the drug.23 Researchers 
in one study concluded that administration of 

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TQD was not associated with enhanced toxicity or 
altered blood plasma pharmacokinetics as in the 
case of several other P-gp inhibitors, yet these 
results have not been replicated in similar studies 
nor demonstrate consistency with other findings. 
20 Two studies revealed that, despite the significant 
improvement in seizure activity during the first few 
days of TQD and AED coadministration, TQD 
tolerance eventually developed through unknown 
mechanisms.19, 21 These results implicate the need 
for further exploration of the pharmacology of 
TQD in order to reduce tolerance to the 
drug. TQD could potentially lead to toxicity in 
organs other than the brain, such as the intestines, 
liver, and kidneys by inhibiting the efflux effect of 
P-gps expressed in those organs as well.17 More
knowledge on the adverse events of TQD is
necessary to ensure its safety in the clinical setting.
Additionally, since current research predominantly
considers the effects of TQD for two types of
AEDs (phenobarbital and phenytoin), further
investigation on whether these effects can be
extrapolated to a broader range of AEDs would
provide a more comprehensive treatment method
for refractory epilepsy.
Conclusion 

Refractory epilepsy is a complex, 
multifaceted disease that impacts millions of 
people worldwide. The drug-resistant nature of 
this condition poses unique challenges for 
physicians attempting to provide therapeutic care 
to patients and establishes an urgency for 
researchers to determine its mechanisms. While 
many hypotheses attempt to explain the 
mechanisms of refractory epilepsy, the 
overexpression of P-glycoprotein (P-gps) 
transporters in endothelial cells at the blood brain 
barrier best accounts for pharmacoresistance. 
Across the numerous studies examined within this 
review, a clear relationship was identified between 
the overexpression of P-glycoproteins in epileptic 
brain tissue and reduced uptake of antiepileptic 

drugs (AEDs) at the blood brain barrier. The 
consistent and replicated association between P-
gp overexpression and reduced AED 
concentration demonstrates that, as a result of the 
drug efflux process, P-gp overexpression is the 
primary mechanism of decreased drug efficacy in 
refractory epilepsy patients.  

With P-gp overexpression identified as the 
lead cause of refractory epilepsy, the focus shifts 
towards improving the standard of care for 
refractory epilepsy patients through the proposed 
treatment method of P-gp inhibition. This 
treatment method suggests that the co-
administration of an AED and P-gp inhibitor 
reduces the efflux effects of P-gp and allows for 
increased AED uptake at the blood brain barrier, 
thereby increasing the therapeutic effect of the 
drug. Two P-gp inhibitors, Tariquidar (TQD) 
and Verapamil, have been identified as potential 
treatment options. However, due to the lack of 
evidence supporting Verapamil s efficacy, it has�
been determined that TQD poses the most 
promise as an effective treatment option for 
refractory epilepsy. Many studies examined within 
this review showed that when co-administered 
with an established AED, TQD led to increased 
AED concentration in brain tissue and, thus, 
greater drug efficacy. Despite these promising 
findings, Tariquidar still poses limitations that 
warrant further investigation. Many studies have 
shown that TQD may cause adverse events such as 
tolerance and toxicity. Additionally, very few 
studies using human subjects have been conducted 
on TQD inhibitors and their effect with various 
AEDs. With these limitations and gaps in 
knowledge, the need for more clinical trials 
specifically investigating the effects of TQD and 
other P-gp inhibitors such as Verapamil is clear. 
In addition, future studies should be conducted to 
determine the mechanisms of TQD tolerance and 
toxicity in order to improve the safety and efficacy 
of TQD. Such findings may affirm the ability of 
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