The Effect of Uridine Diphosphate Glucuronosyltransferase (UGT)1A6 Genetic Polymorphism on Valproic Acid Pharmacokinetics in Indian Patients with Epilepsy: A Pharmacogenetic Approach

Background and Objective Sodium valproate is a widely prescribed broad-spectrum antiepileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. We evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT)1A6 (541A > G, 552A > C) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy. Methods Genotype analysis of the patients was made with polymerase chain-restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration-time data were analyzed by using a non-compartmental approach. Results The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A6 (541A > G) or UGT1A6 (552A > C) polymorphic enzymes. The elimination half-life (t (A1/2) = 40.2 h) of valproic acid was longer and the clearance rate (CL = 917 ml/h) was lower in the poor metabolizers group of UGT1A6 (552A > C) polymorphism who showed toxicity than in the intermediate metabolizers group (t (A1/2) = 35.5 h, CL = 1,022 ml/h) or the extensive metabolizers group (t (A1/2) = 25.4 h, CL = 1,404 ml/h). Conclusion Our findings suggest that the UGT1A6 (552A > C) genetic polymorphism plays a significant role in the steady state concentration of valproic acid, and it thereby has an impact on the toxicity of the valproic acid used in the patients with epilepsy.