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The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: A pharmacogenetic approach

Arumugam, Karthik and Rajakannan, T and Mallayasamy, SR (2013) The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: A pharmacogenetic approach. Molecular diagnosis & therapy, 17 (5). pp. 319-326.

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Abstract

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� = 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� = 35.5 h, CL = 1,022 ml/h) or the extensive metabolizers group (t� = 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.

Item Type: Article
Subjects: Pharmacy > MCOPS Manipal > Pharmacy Practice
Depositing User: KMC Manipal
Date Deposited: 17 Jan 2014 11:02
Last Modified: 17 Jan 2014 11:17
URI: http://eprints.manipal.edu/id/eprint/138442

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