Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

/pdf/drug-resistant-epilepsy-multiple-hypotheses-few-answers-5d2k3761sz.pdf

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

https://cyberleninka.org/article/n/719862.pdf

Pharmacogenomics in epilepsy

Background: Biliary excretion is a major elimination route of many drugs and their metabolites. Hepatobiliary elimination is a vectorial process involving uptake transporters in the basolateral hepatocyte membrane, possibly Phase I and Phase II metabolizing enzymes, and ATP-dependent efflux pumps in the apical hepatocyte membrane. Objectives: Because many drugs and their metabolites are anions, this review focuses on transporters involved in their hepatocellular uptake (members of the organic anion transporting polypeptide (OATP) family) and biliary elimination (apical conjugate efflux pump ABCC2/MRP2). Methods: The molecular and functional characteristics of the human OATP and ABCC/MRP transporters are presented, including a detailed overview of endogenous and drug substrates. Examples illustrate the interplay of transporters with Phase II conjugating enzymes. Model systems to study the vectorial transport of organic anions are also discussed. Results/conclusions: OATP uptake transporters, conjugating en...

Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs

The historical phasing concept of drug metabolism and elimination was introduced to comprise the two phases of metabolism: phase I metabolism for oxidations, reductions and hydrolyses, and phase II metabolism for synthesis. With this concept, biological membrane barriers obstructing the accessibility of metabolism sites in the cells for drugs were not considered. The concept of two phases was extended to a concept of four phases when drug transporters were detected that guided drugs and drug metabolites in and out of the cells. In particular, water soluble or charged drugs are virtually not able to overcome the phospholipid membrane barrier. Drug transporters belong to two main clusters of transporter families: the solute carrier (SLC) families and the ATP binding cassette (ABC) carriers. The ABC transporters comprise seven families with about 20 carriers involved in drug transport. All of them operate as pumps at the expense of ATP splitting. Embedded in the former phase concept, the term "phase III" was introduced by Ishikawa in 1992 for drug export by ABC efflux pumps. SLC comprise 52 families, from which many carriers are drug uptake transporters. Later on, this uptake process was referred to as the "phase 0 transport" of drugs. Transporters for xenobiotics in man and animal are most expressed in liver, but they are also present in extra-hepatic tissues such as in the kidney, the adrenal gland and lung. This review deals with the function of drug carriers in various organs and their impact on drug metabolism and elimination.

Phase 0 and phase III transport in various organs: combined concept of phases in xenobiotic transport and metabolism.

Aim: The aim of this study was to evaluate the association of genetic variants in the major genes involved in carbamazepine (CBZ) metabolism and transport with its pharmacokinetics in epilepsy patients. Materials & methods: Twenty-five SNPs within seven CBZ pathway genes, namely CYP3A4, CYP3A5, EPHX1, NR1I2, UGT2B7, ABCB1 and ABCC2, were analyzed for association with CBZ pharmacokinetics in 90 epilepsy patients. Results: The CYP3A4*1B SNP was significantly associated with CBZ clearance. Significant association of EPHX1 SNPs was observed with greater carbamazepine-10,11-trans dihydrodiol:carbamazepine 10-11 epoxide ratios. Among drug transporters, ABCB1 and ABCC2 SNPs were significantly associated with altered CBZ clearance. Conclusion: SNPs within CBZ pathway genes contribute to interpatient variation in CBZ pharmacokinetics and might contribute to pharmacoresistant epilepsy. Although our results need further clinical validation in a larger patient cohort, they indicate that genetic variation in CBZ pathw...

Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy.

Objectives – Interindividual variability in intestinal absorption and bioavailability might contribute to inadequate control of seizures under treatment with carbamazepine and phenytoin. We therefore correlated intestinal expression levels and genetics of CYP3A4, CYP2C9/19, MDR1 and MRP2 with dose requirement and plasma levels of carbamazepine and phenytoin.



Materials and methods –  Epileptic patients on carbamazepine (n = 29) or phenytoin (n = 15) were stratified into a ‘high’-dose (carbamazepine ≥800 mg/day, phenytoin ≥300 mg/day) and a ‘low’-dose group (carbamazepine ≤600 mg/day, phenytoin ≤200 mg/day). Duodenal biopsies and DNA were obtained for Western blotting and genotyping studies.



Results –  Low carbamazepine plasma levels showed a trend towards higher intestinal MDR1 expression (P = 0.06). Furthermore, carbamazepine dose was positively correlated with MRP2 expression (P = 0.1). Moreover, MDR1 expression and carbamazepine and phenytoin dose requirement was influenced by the genotype in position 2677 and 3435 of the MDR1 gene.



Conclusion –  Differences in intestinal MDR1 and MRP2 expression may influence carbamazepine and phenytoin disposition and may account for interindividual pharmacokinetic variability.

Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition

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Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition