Drug resistance in epilepsy and the ABCB1 gene: The clinical perspective

Abstract

Multidrug resistance is one of the most serious problems in the treatment of epilepsy that is likely to have a complex genetic and acquired basis. Various experimental data support the hypothesis that over-expression of antiepileptic drug (AED) transporters may play a pivotal role in drug resistance. Hyyt 6however, key questions concerning their functionality remain unanswered. The idea that P-glycoprotein, encoded by the ABCB1 gene, might mediate at least part of the drug resistance was met with both enthusiasm and skepticism. As in oncology, initial optimism has been clouded subsequently by conflicting results. The first study reporting a positive association between genetic variation in the P-glycoprotein and multidrug-resistant epilepsy was published in 2003. Since then, several other genetic association studies have attempted to verify this result. However, taken overall, the role of P-glycoprotein in drug resistance in epilepsy still remains uncertain. We intend to critically review the inherent problems associated with epilepsy pharmacogenetic studies in general and with ABCB1 polymorphisms studies in particular. The lessons learnt from the ABCB1 studies can help us to guide future association genetics studies to investigate AED resistance, and thereby taking us closer to the cherished dream of personalized AED therapy.

Keywords: ABCB1; P-glycoprotein; antiepileptic drugs; drug resistance; epilepsy; genetic association studies; genome-wide association studies; single nucleotide polymorphism.

Figure 1

The structure of P-glycoprotein: The structure of P-glycoprotein that transports drugs out of the cell, which is a process that requires the presence of two ATP-binding domains. These domains are a defining characteristic of this family of ATP-binding cassette (ABC) transporters. The exact mechanism of drug efflux is not well understood, but might involve either direct transport out of the cytoplasm or redistribution of the drug as it transverses the plasma membrane. AEDs, anti-epileptic drugs