Here, we performed the first haplotype meta-analysis to examine the association of haplotypes of ABCB1 common variants with the response to treatment in epilepsy.
rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB.
Indeed, many genes, including genes encoding drug transporters (ABCB1), drug targets (SCN1A), drug-metabolizing enzymes (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins, may regulate the mechanisms of drug resistance in epilepsy.
Selective inhibitors of the major efflux transporter P-glycoprotein are currently in clinical trials for reversing chemotherapy resistance in oncology and may soon be used to determine whether such inhibitors can prevent or reverse drug resistance in epilepsy.
The genetic polymorphism of ABCB1rs1045642 was found to be associated with normalized OXC concentration and therapeutic efficacy in patients with epilepsy (P<0.05).
Genetic polymorphisms of the P-glycoprotein-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients.
As compared with patients with drug-responsive epilepsy, patients with drug-resistant epilepsy were more likely to have the CC genotype at ABCB1 3435 than the TT genotype (odds ratio, 2.66; 95 percent confidence interval, 1.32 to 5.38; P=0.006).
Since P-glycoproteins control the extrusion of a broad range of toxins and xenobiotics and are responsible for drug resistance in many diseases including cancer and brain diseases such as epilepsy, we propose that the failure of NDGA in maintaining glutamate uptake upregulated in SOD1-G93A mice and its therapeutic inefficacy are due to acquired pharmacoresistance mediated by the increased expression of P-glycoprotein.
Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy.-Soldner, E. L. B., Hartz, A. M. S., Akanuma, S.-I., Pekcec, A., Doods, H., Kryscio, R. J., Hosoya, K.-I., Bauer, B. Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier.
The present study attempted to evaluate association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and P-gp activity with treatment response in patients with epilepsy.
Our aim was to investigate the effect of the 1236C>T(rs1128503), 2677G>T/A(rs2032582), and 3435C>T(rs1045642) single-nucleotide polymorphisms of ABCB1 (or MDR1) on drug resistance in north Indian patients with epilepsy.
These findings rule out the MDR1 c.3435C>T polymorphism having a major role or increasing the risk of drug-resistance suggesting a revision is required to determine the contribution of this polymorphism in predicting drug response in epilepsy.
Furthermore, patients with symptomatic epilepsies with the ABCB1_3435CT or TT genotypes had a lower risk of drug-resistance than those with the CC genotype.
In this case-control study, we have investigated the role of ABCB1rs1045642 and rs2032582 and ABCC2 rs2273697 and rs717620 single nucleotide polymorphisms in antiepileptic drug-resistance in patients with epilepsy.
By compared to the epilepsy model group, the P-gp expression was not markedly attenuated by the inhibition of NF-κB activity with PDTC treatment, nevertheless with a decrease of NF-κB expression in this intervention group.
Neuroinflammation due to high levels of glutamate has been identified as one of the causes of P-gp upregulation, and several studies in animal models of epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of refractory epilepsy.
However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004).
In addition to Pgp, increased expression of several multidrug resistance-associated proteins (MRPs) has been determined in epileptogenic brain regions of patients with pharmacoresistant epilepsy.
P-glycoprotein (Pgp), a transmembrane transporter encoded by ABCB1 gene and located at the endothelial cells of the blood-brain barrier (BBB), has been associated with epilepsy pharmacoresistance.