Effects of UGT1A6, UGT2B7, and CYP2C9 Genotypes on Plasma Concentrations of Valproic Acid in Chinese Children with Epilepsy

Abstract

  Valproic acid (VPA) is one of the most commonly prescribed drugs for the treatment of epilepsy. Interindividual variability in VPA dose and plasma concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between plasma concentrations of VPA and single nucleotide polymorphisms (SNPs) involving uridine diphosphate glucuronosyltransferase (UGT) 1A6 (UGT1A6), UGT2B7, and cytochrome P450 2C9 (CYP2C9) genes in Chinese children with epilepsy. UGT1A6, UGT2B7, and CYP2C9 polymorphisms were identified by the polymerase chain reaction-restriction fragment length polymorphism approach or direct automated DNA sequencing in 98 epileptic patients treated with VPA monotherapy. Patients with double heterozygosities at nucleotide positions T19G, A541G and A552C in the UGT1A6 gene, were associated with higher VPA doses compared to those with wild type or single heterozygosity (p = 0.010). Lower adjusted plasma VPA concentrations were also observed in patients with UGT1A6 double heterozygosities than those with single heterozygosity (p = 0.027). There were no differences in VPA dose or adjusted plasma VPA concentrations among the UGT2B7*2 or CYP2C9*3 genotypic groups. These results suggest that UGT1A6 mutations affect VPA metabolism in epileptic children. It needs to be further investigated in a larger cohort of patients.