Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects.

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Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects.

Br J Clin Pharmacol. 2007 Jul;64(1):67-74. Epub 2007 Feb 12.

PubMed ID

17298483 [ View in PubMed

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Abstract

AIMS: To investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release (MR) in healthy Chinese subjects. METHODS: In a single-dose pharmacokinetic study, 24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose. In a multiple-dose pharmacokinetic study, 17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose. The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method. CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: In the single-dose study, no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1, *1/*3 and *1/*13 subjects. In contrast, the AUC(0-infinity) of gliclazide was significantly increased by 3.4-fold [95% confidence interval (CI) 2.5, 4.7; P < 0.01] in CYP2C19 poor metabolizer (PM) subjects compared with CYP2C19*1 homozygotes. The half-life (t(1/2)) was prolonged from 15.1 to 44.5 h (P < 0.01). Similar differences were found in the multiple-dose study. The parameters of gliclazide AUC(ss), AUC(0-infinity) and C(max) were 3.4-fold (95% CI 2.9, 4.0), 4.5-fold (95% CI 3.8, 5.4) and 2.9-fold (95% CI 2.4, 3.4) increased (P < 0.01) in CYP2C19 PM subjects, respectively, compared with CYP2C19*1 homozygotes, and t(1/2) was increased from 13.5 to 24.6 h (P < 0.01). CONCLUSIONS: The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Gliclazide	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate	Details

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2	(A;A) / (A;G)	681G>A (rs4244285)	Effect Directly Studied	The presence of this polymorphism in CYP2C19 is associated with reduction in gliclazide metabolism.	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*3	Not Available	636G>A (rs4986893)	Effect Directly Studied	The presence of this polymorphism in CYP2C19 is associated with reduction in gliclazide metabolism.	Details