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

Tan, Lan; Yu, Jin-Tai; Sun, Yan-Ping; Ou, Jiang-Rong; Song, Jing-Hui; Yu, Yang

doi:10.1016/j.clineuro.2010.01.002

« Previous Next »Clinical Neurology and Neurosurgery
Volume 112, Issue 4 , Pages 320-323, May 2010

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

Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province 266071, China
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine and Pharmaceutics, Ocean University of China, 266071, China
- Corresponding author at: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. Tel.: +86 532 8890 5659; fax: +86 532 85968434.
Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province 266071, China
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine and Pharmaceutics, Ocean University of China, 266071, China
Yan-Ping Sun
- Department of Neurology, the Affiliated Hospital of the Medical College of Qingdao University, Qingdao 266003, Shandong Province, China
Jiang-Rong Ou
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province 266071, China
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine and Pharmaceutics, Ocean University of China, 266071, China
Jing-Hui Song
- Department of Neurology, the Affiliated Hospital of the Medical College of Qingdao University, Qingdao 266003, Shandong Province, China
Yang Yu
- Department of Neurology, the Affiliated Hospital of the Medical College of Qingdao University, Qingdao 266003, Shandong Province, China

Received 15 April 2009; received in revised form 10 November 2009; accepted 5 January 2010.

Abstract

Objectives

To 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 methods

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).

Results

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)μgkgml⁻¹mg⁻¹ vs. (3.6±0.4)μgkgml⁻¹mg⁻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)μgkgml⁻¹mg⁻¹ vs. (3.4±0.4)μgkgml⁻¹mg⁻¹, p=0.0001].

Conclusion

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.

Keywords: Cytochrome P450, Genetic polymorphism, Valproic acid, Plasma concentration, Epilepsy