Resistance In Epilepsy Research Articles

ABCB1 Gene C3435T Polymorphism and Drug Resistance in Epilepsy: Evidence Based on 8604 Subjects

BackgroundThe present study aimed to assess the role of C3435T polymorphism in drug-resistance in epilepsy by a meta-analysis.Material/MethodsDatabases were obtained from the Cochrane Library, MEDLINE, EMBASE, PubMed, Science Direct database, CNKI, and Wanfang up to October 2014. All the case-control association studies evaluating the role of ABCB1 C3435T in pharmacoresistance to anti-epileptic drug (AED) were identified. RevMan 5.0 software was utilized to perform quantitative analyses in an allele model (C vs. T) and a genotype model (CC vs. CT+TT).ResultsFrom the 189 potential studies, we included 28 articles for the meta-analysis, including 30 independent case-control studies involving 4124 drug-resistant epileptic patients and 4480 epileptic patients for whom drug treatment was effective. We excluded 164 studies because of duplication, lack of genotype data, and non-clinical research. We found that C3435T polymorphism was not significantly associated with drug resistance in epilepsy, either in allele model (C vs. T: OR=1.07; 95%CI: 0.95–1.19) or in genotype model (CC vs. CT+TT: OR=1.05; 95%CI: 0.89–1.24, P=0.55). Subgroup analyses suggested that in Caucasian populations there are significant differences between resistance group (NR) and control group (R) in both allele model (C vs. T: OR=1.09; 95%CI: 1.00–1.18, P=0.05) and genotype model (CC vs. CT+TT: OR=1.20; 95%CI: 1.04–1.40, P=0.01). However, we did not find this association in Asian populations.ConclusionsWe conclude that the ABCB1 C3435T polymorphism may be a genetic marker for drug resistance in epilepsy in Caucasian populations.

Neuroimaging of drug resistance in epilepsy

Drug resistance is an important clinical problem: it is associated with higher rates of somatic and psychiatric comorbidities and cognitive/memory decline, with seizures being just the 'tip of the iceberg'. This review summarizes recent developments in imaging research, focusing specifically on the functional consequence of chronic epilepsies and mechanisms of drug resistance, restricted to work published in 2013. Functional imaging approaches reliably identify underlying specific networks in patients with different epileptic syndromes, show specific responses to certain antiepileptic drugs and differentiate between responder and nonresponder. Functional MRI (fMRI) and the intracarotid amobarbital test (IAT) are generally congruent, but fMRI may be more sensitive than IAT to right hemisphere language processing. In addition, memory fMRI supports the functional adequacy of ipsilateral structures rather than functional reserve of the contralateral hemisphere. There is further evidence from group analysis of fMRI data for a node within the ipsilateral piriform cortex to be important for seizure modulation in focal refractory epilepsies of different cortical origin. Molecular imaging with verapamil-PET identifies P-glycprotein overexpression as a mechanism contributing to drug resistance in individual patients. Neuroimaging in epilepsy has progressed from correlations with demographic, semiologic, neuropsychological and other observational data primarily in patients undergoing presurgical investigations to imaging network connectivity changes in epilepsy syndromes, and testing specific mechanisms underlying drug-resistant epilepsy.

Polymorphism of ABCB1/MDR1 C3435T in children and adolescents with partial epilepsy is due to different criteria for drug resistance - preliminary results.

BackgroundThe diagnosis of “drug resistance” in epilepsy can be defined and interpreted in various ways. This may be due to discrepant definitions of drug resistance to pharmacotherapy.The aim of our study was to investigate the relationship between C3435T polymorphism of the MDR1 gene and drug resistance in epilepsy with the consideration of 4 different criteria for qualification to groups sensitive and resistant to applied pharmacotherapy.Material/MethodsEvaluation of C3435T polymorphism of MDR1/ABCB1 gene was conducted on a group of 82 white children and young adolescents up to 18 years old. While qualifying the patients to the group of sensitive or drug resistant, the following 4 definitions of drug resistance were applied: the ILAE’s, Appleton’s, Siddiqui’s, and Berg’s.ResultsA detailed analysis of genotypes of the MDR1 gene did not show any significant discrepancies between the groups of patients resistant and sensitive to antiepileptic drugs (AEDs) in 4 consecutive comparisons taking into consideration various criteria of sensitivity and resistance to pharmacotherapy.ConclusionsThe obtained results clearly confirm the lack of a connection between the occurrence of drug-resistant epilepsy and C435T polymorphism of the MDR1 gene irrespective of the definition of drug resistance applied to the patient.

The Effects ofABCC2G1249A Polymorphism on the Risk of Resistance to Antiepileptic Drugs: A Meta-Analysis of the Literature

The G1249A variant of the multidrug resistance-associated protein 2 (ABCC2) gene may be associated with the development of antiepileptic drug (AED) resistance. Although numerous studies have investigated the association between the G1249A variant and the risk of drug resistance in epilepsy, the results of these studies have been inconclusive. To assess the role of G1249A polymorphism in drug resistance in epilepsy, a meta-analysis was performed. We systematically reviewed relevant studies retrieved by the PubMed and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the date extracted from the studies to evaluate the strength of association. We also analyzed the heterogeneity and sensitivity of each report and the publication bias of the studies. A total of 6 published studies, involving 2213 patients (1100 patients with drug-resistant epilepsy and 1113 controls with drug-responsive epilepsy) were reviewed in the present meta-analysis. The overall results indicated that the variant genotypes were associated with a significantly decreased risk of AED resistance (AA vs. GG: OR=0.372, 95% CI=0.182-0.762; recessive model: OR=0.399, 95% CI=0.200-0.795) (fixed-effects model). A stratified analysis by ethnicity showed similar findings for Caucasians in an additive model (A vs. G: OR=0.700, 95% CI=0.494-0.992). The meta-analysis suggests that the ABCC2 G1249A polymorphism is significantly associated with a decreased risk of AED resistance. However, further functional investigations are warranted to validate the association.

The drug-transporter gene MDR1 C3435T and G2677T/A polymorphisms and the risk of multidrug-resistant epilepsy in Turkish children

One-third of all individuals with epilepsy are resistant to antiepileptic drug (AED) treatment. Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters. Several polymorphic variants within the multidrug resistance 1 (MDR1) gene, which encodes the major transmembrane efflux transporter P-glycoprotein, have been proposed to be associated with AED resistance in epilepsy patients. The aim of this study was to evaluate the effect of C3435T and G2677T/A polymorphisms of MDR1 on AED resistance in Turkish children with epilepsy. MDR1 C3435T and G2677T/A were genotyped in 152 patients with epilepsy, classified as drug-resistant in 69 and drug-responsive in 83. Genotypes of the C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction followed by restriction fragment length polymorphism. Genotype and allele frequencies of C3435T and G2677T/A polymorphisms of the MDR1 gene did not differ between drug-resistant and drug-responsive epilepsy patients. Our results suggest that MDR1 C3435T and G2677T/A polymorphisms are not associated with AED resistance in Turkish epileptic patients. To clarify the exact clinical implication of the MDR1 polymorphisms on the multidrug resistance in epilepsy, further investigations in various ethnic populations would be necessary.

Imaging P-glycoprotein function in rats using [11C]-N-desmethyl-loperamide

One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [(11)C]N-desmethyl-loperamide ([(11)C]dLop), for measuring P-gp function in the rat brain. The precursor to [(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [(11)C]methyl iodide. [(11)C]dLop was then administered to two groups of rats, controls (n=4) and those treated with a P-gp inhibitor (n=8). Cyclosporin A (CsA, 50mg/kg, n=3) and tariquidar (TQ, 20mg/kg, n=5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function. Plasma levels of parent [(11)C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60min. In controls, brain uptake of [(11)C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA=7.3, TQ=4.7) compared to controls (no inhibitor=2.1). The rat brain demonstrates significantly increased uptake of [(11)C]dLop after P-gp inhibition. [(11)C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.

Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review

Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review

Interleukin-1β causes fluoxetine resistance in an animal model of epilepsy-associated depression.

Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

Lack of Association Between ABCC2 Gene Variants and Treatment Response in Epilepsy

The aim of this study was to replicate a previously reported association between drug resistance in epilepsy patients and the 24C>T variant of the ABCC2 gene that codes for the drug efflux transporter MRP2. We genotyped 381 Caucasian epileptic patients (337 drug resistant and 44 drug responsive) and 247 healthy controls for the ABCC2 gene -24C>T polymorphism (rs717620) and two other nearby SNPs in linkage disequilibrium (1249G>A and 3972C>T). Genotype, allele and three-SNP-haplotype frequencies were compared between groups. Patients were further stratified into four groups according to their degree of drug resistance (as measured by seizure frequency under medication) to perform regression analysis against genotypes and haplotpyes. We detected no significant differences in the distribution of any of the tested alleles, genotypes or haplotypes between the investigated groups. Neither was there an association between genotypes or haplotypes and degree of drug resistance. This study was adequately powered to detect genotype relative risks of above two. Although adequately powered to detect the previously reported effect size and although our definition of drug resistance, following the International League Against Epilepsy guidelines, was slightly stricter than in the original study, we failed to confirm an association between the 24C>T variant in the ABCC2 gene and drug resistance in epilepsy.

Correlation study on expression of GST-π protein in brain tissue and peripheral blood of epilepsy rats induced by pilocarpine

Previous studies have suggested that glutathione-S-transferase π (GST-π) over-expression in the brain tissue is associated with refractory epilepsy. However, whether the change in GST-π level in the peripheral blood is in line with that in brain tissue remains unknown. This study examined the correlation between GST-π in brain tissue and that in peripheral blood in rat models of pilocarpine-induced refractory epilepsy. The animals were divided into drug-resistant group and drug-responsive group according to the response to anti-epileptic drugs. GST-π expression in brain tissue was immunohistochemically determined, while the expression of GST-π in peripheral blood was analyzed by Western blotting. In the hippocampus and cortex, GST-π was mainly found in the cytoplasm and membrane of neurons, and the GST-π expression level was higher in drug-resistant group than in the drug-responsive group and saline control group (P<0.05). Moreover, there was no significant difference between responders and saline control animals (P>0.05). The change in expression of GST-π in peripheral blood showed the same pattern as that in brain tissues, suggesting GST-π might contribute to drug resistance in epilepsy. Importantly, the GST-π over-expression in peripheral blood could be used as a marker for resistance to anti-epileptic agents.

Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy

P-glycoprotein may play a role in drug resistance in epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). We sought to investigate the effects of ABCB1 polymorphisms on plasma carbamazepine (CBZ) concentrations and pharmacoresistance in Chinese patients with epilepsy. C1236T, G2677T/A, and C3435T polymorphisms of ABCB1 were genotyped by polymerase chain reaction amplification followed by restriction fragment length polymorphism analysis or direct automated DNA sequencing in 84 patients treated with CBZ monotherapy. Patients with 3435-TT ( n = 15) had lower adjusted CBZ concentrations than those with 3435-CC ( n = 30) ( P = 0.026). However there were no associations between all the studied genotypes, haplotypes, or diplotypes involving ABCB1 C1236T, G2677T/A, and C3435T polymorphisms and pharmacoresistance in the patient cohort. Our results suggest that ABCB1 3435-TT is associated with decreased plasma CBZ levels in Chinese patients with epilepsy. However, whether this contributes to CBZ resistance needs to be further investigated in a larger cohort of patients.

Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs). Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment. Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs. One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T > G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P(raw) = .0025). A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.

Gene-Wide Tagging Study of the Association Between ABCC2 , ABCC5 and ABCG2 Genetic Polymorphisms and Multidrug Resistance in Epilepsy

To determine the association between polymorphisms of the multidrug transporter genes ABCC2, ABCC5 and ABCG2, and drug resistance in epilepsy by genotyping comprehensive sets of tagging SNPs. A total of 25 tagging SNPs from ABCC2, ABCC5 and ABCG2 genes were genotyped in a total of 590 Han Chinese epilepsy patients (262 drug resistant and 328 drug responsive). Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. Genotype distributions of all the selected SNPs were consistent with Hardy-Weinberg equilibrium. None of the polymorphisms, either genotype or allele distributions, were significantly associated with drug resistance. For each gene, no haplotypes of over 1% frequency, and that included all SNPs of the gene, were associated with drug resistance. This gene-wide tagging study revealed no association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy.

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

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.

RLIP76 Gene Variants are not Associated with Drug Response in Turkish Epilepsy Patients

Approximately 30% of epileptic patients remain untreated, in spite of trials with maximum tolerable doses of more than one drug. The RalA binding protein 1 (RALBP1/RLIP76), a multifunctional, anti-apoptot-ic, multidrug transporter protein, has been proposed as being responsible for the drug resistance mechanism in epilepsy. We have investigated polymorphic differences in the coding regions and exonintron boundaries of the RLIP76 gene, between 146 refractory and 155 non refractory epileptic patients in Turkey, using denaturing high performance liquid chromatography (HPLC) and sequencing analysis techniques. We have detected the following sequence variants: c.160-4G>A, c.187C>G, c.1562-38G>A, c.1670+107G>A, c.1670+93G>A, c.1670+96G>A, c.1670+100C>T, c.1670+130C>T, c.1670+131G>C, c.1670+140 G>C, and found no statistically significant correlation between allele frequencies and drug response status. We conclude that sequence variants of this gene are not involved in drug resistance in epilepsy.

Drug resistance in epilepsy

SummaryDrug resistance remains one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel drugs and therapeutic strategies for difficult‐to treat epilepsies. For an expanded treatment of this topic see Jasper’s basic mechanisms of the epilepsies. 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

Transporter Hypothesis of Drug-Resistant Epilepsy: Challenges for Pharmacogenetic Approaches

Drug resistance in epilepsy is considered a complex and multifactorial problem. Overexpression of efflux transporters at the blood-brain barrier is discussed as one factor that might limit brain penetration and efficacy of antiepileptic drugs. Whereas experimental data render support for this hypothesis, there is still a lack of sufficient clinical evidence indicating a functional role of efflux transporters. Pharmacogenetic analysis has been considered as one approach in the evaluation of a putative link between transporters and drug-resistant epilepsy. However, the likelihood of a multifactorial nature of drug resistance and the complexity of the events regulating transporters pose a major challenge to any attempt at linking selected genetic polymorphisms to the outcome of drug therapy. In this article, the evidence for an impact of efflux transporters on the response to antiepileptic drugs is discussed, focusing in particular on the different issues presenting a challenge for pharmacogenetic approaches in this field.

Multidrug Resistance 1 (MDR1) Gene Polymorphisms in Childhood Drug-Resistant Epilepsy

Despite considerable progress in the pharmacotherapy of epilepsy, more than 30% of patients are reported to be resistant to antiepileptic drugs. Multidrug resistance 1 (MDR1) gene could play a role in drug resistance in epilepsy. In this study, the authors investigated the association between the MDR1 gene polymorphisms, C3435T and G2677AT, and drug resistance epilepsy by using polymerase chain reaction/restriction fragment length polymorphism and pyrosequencing methods in a group of 39 patients with drug-resistant epilepsy and 92 controls. No associations were found between the polymorphisms of the MDR1 gene and drug-resistant epilepsy. Haplotype analysis showed no significant association. Compound genotype analysis showed that CC3435/GG2677 was significantly higher in the control group compared to the patient group. In conclusion, MDR1 polymorphisms investigated in this study are not associated with antiepileptic drug resistance, but the CC3435/GG2677 compound genotype might have an effect on antiepileptic drug response.

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

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].

Gene-Wide Tagging Study Of Association Between ABCB1 Polymorphisms and Multidrug Resistance in Epilepsy in Han Chinese

It remains controversial whether polymorphisms of the multidrug resistance gene ABCB1 are associated with pharmacoresistance in epilepsy. To further study the potential association, we genotyped a broad set of tagging SNPs, and explored whether any associations were affected by other host factors. We correlated any association with cerebral mRNA expression of ABCB1. A total of 12 tagging and candidate SNPs of ABCB1 were genotyped in 464 Chinese epilepsy patients (270 drug responsive, 194 drug resistant). Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. ABCB1 mRNA was quantified by real-time PCR in brain samples resected from 20 patients with drug-resistant epilepsy. Its level was compared between patients with different genotypes of ABCB1 SNPs found to be associated with drug resistance. The intronic polymorphism rs3789243 (p = 0.009 for allele analysis) and the coding polymorphism 2677G/T/A (p = 0.02), and haplotypes containing them, were associated with drug resistance. The 2677G/T/A genotypes remained significantly associated with drug resistance after multiple logistic regression and correction for multiple comparisons. The associations with drug resistance were found in males (p = 0.004 for rs3789243 and p = 0.0007 for 2677T/A>G) but not females, and in patients with localization-related (p = 0.006 for rs3789243 and p = 0.01 for 2677T/A>G) but not idiopathic-generalized epilepsy. ABCB1 mRNA levels did not correlate with genotypes. In Chinese epilepsy patients, the ABCB1 intronic polymorphism rs3789243 and the coding polymorphism 2677, and haplotypes containing them, may be associated with drug resistance, without an effect on mRNA expression. There was preliminary evidence of interactions between these polymorphisms and gender and epilepsy syndrome.