The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients

ObjectivesTo investigate influences of the functional polymorphisms of Cytochrome P450 isozymes 2A6 (CYP2A6), 2B6 (CYP2B6), and 2C9 (CYP2C9) on pharmacokinetics of VPA in vivo.Patients and methodsIn the study, we analyzed the genotypes of CYP2A6, CYP2B6, and CYP2C9 and their contribution to the steady-state standardized plasma VPA concentrations in 179 subjects with epilepsy of a Northern Han Chinese population. The genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).ResultsThe subjects with one or two variant CYP2A6*4 alleles showed higher mean plasma VPA concentrations compared with non-*4 alleles [(3.4 ± 0.4) μg kg ml−1 mg−1 vs. (3.6 ± 0.4) μg kg ml−1 mg−1, p = 0.0055]. A significant difference [one-way ANOVA (p = 0.0203)] was also found between mean plasma VPA concentrations and the CYP2B6 genotypes. In addition, subjects with the heterozygous genotype CYP2C9*3 had higher mean plasma VPA concentrations than did those subjects with the wild-type genotype [(3.9 ± 0.4) μg kg ml−1 mg−1 vs. (3.4 ± 0.4) μg kg ml−1 mg−1, p = 0.0001].ConclusionThe presently evaluated variant alleles in the CYP2A6, CYP2B6, and CYP2C9 genes may explain part of the substantial variability in VPA pharmacokinetics between different subjects.