MDR1/ABCB1 Polymorphisms and Multidrug Resistance In Epilepsy: in and out of Fashion

Abstract

been satisfied for the transporter hypothesis, however, only in rodent models of epilepsy as yet [7]. Accordingly, P-gp expression is: increased in epileptogenic brain tissue of rodents; associated with lower brain levels of AEDs; higher in AED-resistant rats than in responsive animals; and most importantly, co-administration of the highly selective P-gp inhibitor, tariquidar, reverses AED resistance. Thus, it is reasonable to conclude that P-gp plays a significant role in mediating resistance to AEDs in rodent models of temporal lobe epilepsy and that inhibition of P-gp can circumvent this mechanism – however, whether this phenomenon extends to at least some human refractory epilepsy remains unclear [7]. Increased brain expression of efflux transporters, such as P-gp, could be a result either of prolonged or frequent seizures, as demonstrated in rodent models of epilepsy, or of genetic factors, such as polymorphisms in the ABCB1 gene or, theoretically, of both [2]. Siddiqui et al. were the first to report that a SNP in the ABCB1 gene is associated with resistance to multiple AEDs, leading to the suggestion that drug resistance in epilepsy might be genetically determined [8]. In this study, patients with AED-resistant epilepsy were more likely to have the CC genotype at the ABCB1 C3435T polymorphism, which is associated with increased expression of the protein, than the TT genotype [8]. Since then, different studies of various designs have tried to confirm the association between the 3435C>T polymorphism and AED resistance in epilepsy, but most of these subsequent studies were negative [9]. A recent meta-ana lysis of 11 case–control studies involving 3371 patients (1646 patients with drug-resistant epilepsy and 1725 controls) did not identify a significant association between AED resistance and ABCB1 polymorphisms, including the 3435 SNP [10]. However, in most of these pharmacogenetic studies, patients were treated with various AEDs, ignoring the fact that not all AEDs are substrates Resistance to multiple anti-epileptic drugs (AEDs) is a significant problem in epilepsy affecting at least 30% of patients with this common and often devastating disease [1]. One prominent hypothesis to explain this multidrug resistance suggests an inadequate penetration or excess efflux of AEDs across the blood–brain barrier (BBB) as a result of overexpressed efflux transporters, such as P-glycoprotein (P-gp), the encoded product of the multidrug resistance-1 (MDR1, ABCB1) gene [2]. Drug efflux transporters such as P-gp have a major impact on the pharmacological behavior of most clinically used drugs, critically affecting drug absorption, disposition and elimination in the body [3]. The idea that enhanced BBB expression of P-gp could be involved in AED resistance was first proposed by Tishler et al. in 1995, who reported that P-gp and ABCB1 are markedly increased in brain tissue of pa tients with medically intractable partial epilepsy [4]. This finding was subsequently confirmed by several other groups and formed the basis of the transporter hypothesis of intractable epilepsy [5].