Epilepsia

Drug Metab. Pharmacokinet. 27 (5): 536­542 (2012).

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Note
Effects of UGT1A6, UGT2B7, and CYP2C9 Genotypes on Plasma
Concentrations of Valproic Acid in Chinese Children with Epilepsy
Yingjie G UO 1 , Cheng H U 2, Xiaojing H E 3 , Feng Q IU 3 and Limei Z HAO 3, *
1

The State Engineering Laboratory of AIDSVaccine, College of Life Science, Jilin University, Changchun, China
2
School of Biological and Agricultural Engineering, Jilin University, Changchun, China
3
Shengjing Hospital, China Medical University, Shenyang, China

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk
Summary: Valproic acid (VPA) is one of the most commonly prescribed drugs for the treatment ofepilepsy.
Interindividual variability in VPA dose and plasma concentration may re fl ect 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 identi fi ed 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 andA552C 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 orCYP2C9 * 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.
Keywords: epilepsy; valproic acid; genetic polymorphisms; UGT1A6; UGT2B7; CYP2C9

imately 20®70% of a dose of VPA is excreted in the urine
as glucuronide conjugates. CYP-catalyzed metabolism of
VPA accounts forabout 10% of the administrated dose,
mainly mediated by CYP2C9.4¥ The genes coding VPAmetabolizing enzymes are highly polymorphic. It has been
reported that the three most common single nucleotide
polymorphisms in the coding region of the UGT1A6 gene are
T19G, A541G and A552C with allele frequencies of 0.238,
0.220, and 0.247, respectively, in the Chinese population.5¥
The combinations ofdifferent variants ¤UGT1A6*2 to *4¥
result in increased glucuronidation activities.6,7¥ UGT2B7*2
with C802T is the most extensively studied UGT2B7 variant
with an allele frequency of 32.8% in the Chinese population.8¥ In terms of the contribution of UGT2B7*2 to
different drug metabolisms, conflicting results have been
reported.9®11¥ CYP2C9*3 with A1075C, the major CYP2C9
variant with an allelefrequency of about 3.3% in the

Introduction
Valproic acid ¤VPA¥ is widely used for treating children
with epilepsy. Although VPA is affordable and effective
in the control of seizures, there is large interindividual
variability in its pharmacokinetics and pharmacodynamics.
Therefore, its plasma concentration needs to be monitored
as a guide of dose adjustment during the course oftherapy.1¥
These differences in VPA dose and plasma concentration
may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes.
The metabolism of VPA involves three major metabolic
pathways, glucuronidation conjugation, mitochrondrial Çoxidation, and CYP-catalyzed terminal desaturation and
hydroxylation.2¥ The most extensive biotransformation pathway for...