Effects Of Genetic Polymorphisms On Carbamazepine Metabolism In Chinese Patients With Epilepsy

Epilepsy is a chronic neurological disease. Drug therapy is the mainmeans to control epilepsy. Carbamazepine (CBZ) is one of the mostprescribed anticonvulsant drugs used for the treatment of epilepticseizures. It has a narrow therapeutic index and requires therapeuticmonitoring for dosage adjustment due to large interindividual variabilityin its pharmacokinetics and pharmacodynamics. However, about one thirdof patients are CBZ resistant.A number of studies demonstrate that some polymorphisms of genesencoding transporters, drug-metabolizing enzymes and/or targets maycontribute to the variabilities of drug metabolism in patients. CBZ exertsits pharmacodynamic effect by blocking voltage-gated sodium channels suchas Nav1.1,1.2(SCN1A,SCN2A), stabilizing neuron cell membranes anddecreasing glutamate release. The main metabolic pathway of CBZ isoxidation by CYP3A4resulting in the active metabolite,10,11-epoxide,which is subsequently transformed by microsomal epoxide hydrolase (EPHX1)to the inactive CBZ-10,11-diol. P450oxidoreductase (POR) transferselectrons from NADPH to CYP3A enzymes to enable their catalytic activity.MDR1and MPR2are encoded by the ABCB1and ABCC2, respectively, andexpressed on the apical membrane of various tissues, which may beresponsible for the restriction of intestinal drug absorption and drugpenetration to the brain. Therefore, functional consequences of geneticpolymorphisms in genes encoding transporters, drug-metabolizing enzymes,and targets of CBZ may influence its metabolism and pharmacoresistance.In the study, we observed the effects of genetic polymorphisms of CYP3A4*1G, EPHX1T337C/A416G, ABCC2-24C>T/1249G>A/3972C>T and SCN1AIVS5-91G>A on plasma CBZ concentrations and pharmacoresistance in83Chinese adult patients with epilepsy. The results showed that patientswith the variant EPHX1A416G genotypes had higher adjusted plasma CBZconcentrations compared to those with the wild type genotype (AG+GG vsAA, P=0.005). Patients with the337-TC/CC genotype of EPHX1had atendency to have increased drug resistance compared to patiens with thewild type genotype (odds ratio≥4.0).Furthermore, the effects of genetic polymorphisms of CYP3A4*1G,POR*28, ABCB1C1236T, G2677T/A and C3435T on plasma concentrations of CBZ,carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-transdihydrodiol (CBZD) in210Chinese pediatric patients with epilepsy werestudied. Statistical analysis revealed that patients carrying3435CCgenotypes were observed to have significantly higher dose-adjusted CBZ,CBZE and CBZD concentrations than3435CT carriers. CYP3A4*1G variantcarriers seemed to have lower dose-adjusted CBZ and CBZE concentrationsthan CYP3A4*1/*1carriers.In summary, our data suggest that certain polymorphisms of CBZ majortransporter and metabolizing enzyme genes could in part influenceinterindividual variability of CBZ metabolism in Chinese patients withepilepsy. This might provide useful genetic information for personalizedCBZ therapy in patients with epilepsy.