Effects of UGT2B7 Genetic Polymorphisms on Serum Concentrations of Valproic Acid in Chinese Children With Epilepsy Comedicated With Lamotrigine.

Abstract

Valproic acid (VPA) is widely used in the treatment of children with epilepsy. Genetic polymorphisms in genes encoding drug-metabolizing enzymes may be an important source of interindividual variability in VPA metabolism. VPA is a substrate of uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7). In this study, we seek to evaluate the effects of genetic polymorphisms of the UGT2B7 gene on serum VPA concentrations in epileptic children comedicated with lamotrigine (LTG). We recruited 166 Chinese children with epilepsy who were treated with VPA in combination with LTG. Serum VPA and LTG concentrations were measured by fluorescence polarization immunoassay and high performance liquid chromatography, respectively. The UGT2B7 -161C > T in the 5'-upstream regions and 211 G > T, 372A > G, 735A > G, and 802C > T in the coding regions were genotyped using polymerase chain reaction amplification followed by direct automated DNA sequencing. Our data show that patients carrying the variant UGT2B7 -161C > T or 802C > T genotypes had significantly higher adjusted VPA concentrations than those carrying the wild-type genotypes. The significant associations were potentiated after adjusted by age and adjusted LTG concentration. However, no associations were detected between the other studied UGT2B7 genotypes and adjusted VPA concentrations, even after adjusting by age and comedication. These results suggest that the UGT2B7 -161C > T or 802C > T mutations affect VPA pharmacokinetics, which are potentially enhanced by age and concomitant LTG administration. These findings provide a potential mechanism underlying interindividual variation in the disposition of VPA in combination with LTG.