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

• Published in: Clinical neurology and neurosurgery Vol. 112; no. 4; pp. 320 - 323
• Main Authors: Tan, Lan, Yu, Jin-Tai, Sun, Yan-Ping, Ou, Jiang-Rong, Song, Jing-Hui, Yu, Yang
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.05.2010; Elsevier; Elsevier Limited
• Subjects: Adolescent; Adult; Alleles; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Brain diseases; Child; Child, Preschool; China - epidemiology; Confidence intervals; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C9; Cytochrome P450; Drug dosages; Epilepsy; Epilepsy - epidemiology; Epilepsy - genetics; Epilepsy - metabolism; Female; Gene Frequency; Genetic polymorphism; Genotype; Humans; Influence; Male; Medical sciences; Metabolism; Metabolites; Middle Aged; Neurology; Neurosurgery; Oxidoreductases, N-Demethylating - genetics; Plasma; Plasma concentration; Polymerase chain reaction; Polymorphism; Polymorphism, Genetic; Statistical analysis; Studies; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Valproic acid; Valproic Acid - blood; Valproic Acid - pharmacokinetics; Young Adult; Valproic acid; Cytochrome P450; Epilepsy; Genetic polymorphism; Plasma concentration; Human; Nervous system diseases; Surgery; Central nervous system disease; Cerebral disorder; Polymorphism
• ISSN: 0303-8467; 1872-6968; 1872-6968
• DOI: 10.1016/j.clineuro.2010.01.002

To investigate influences of the functional polymorphisms of Cytochrome P450 isozymes 2A6 (CYP2A6), 2B6 (CYP2B6), and 2C9 (CYP2C9) on pharmacokinetics of VPA in vivo. In 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). The 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]. The presently evaluated variant alleles in the CYP2A6, CYP2B6, and CYP2C9 genes may explain part of the substantial variability in VPA pharmacokinetics between different subjects.