title: Effects of EPHX1, SCN1A and CYP3A4 genetic polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy.
abstract: The pharmacokinetics and pharmacodynamics of carbamazepine (CBZ) vary widely among patients with epilepsy. In this study, we sought to investigate the effects of genetic polymorphisms of the microsomal epoxide hydrolase (EPHX1), the sodium channel α subunit type I (SCN1A) and the cytochrome P450 3A4 (CYP3A4) genes on plasma CBZ concentrations and pharmacoresistance in Chinese patients with epilepsy. The EPHX1 c.337T>C, c.416A>G, SCN1A IVS5-91G>A or CYP3A4*1G polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism approach or direct DNA sequencing in 83 Chinese patients treated with CBZ monotherapy. Patients with the variant EPHX1 c.416A>G genotypes had higher adjusted plasma CBZ concentrations compared to those with the wild type genotype (P<0.05). In contrast, the SCN1A IVS5-91G>A and CYP3A4*1G variant alleles had no significant effects on CBZ maintenance doses or adjusted CBZ concentrations. There were no associations between all the studied genotypes involving EPHX1 c.337T>C, c.416A>G, SCN1A IVS5-91G>A or CYP3A4*1G polymorphisms and pharmacoresistance in this patient cohort. These results suggest that the EPHX1 c.416A>G polymorphism affects CBZ metabolism in Chinese patients with epilepsy. However, whether it contributes to CBZ resistance needs to be further investigated in a larger cohort of patients.
authors.affiliation: The State Engineering Laboratory of AIDS Vaccine, College of Life Science, Jilin University, Changchun 130021, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Yun
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Luo
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.forename: Hongmei
authors.initials: H
authors.lastname: Meng
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D002220:Carbamazepine / Q000097:blood* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human
keywords: Carbamazepine; Epilepsy; Pharmacoresistance; Plasma concentration; Polymorphism