Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects.
OBJECTIVE
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.
Zhang
Yifan
Y
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Si
Dayong
D
Chen
Xiaoyan
X
Lin
Nan
N
Guo
Yingjie
Y
Zhou
Hui
H
Zhong
Dafang
D
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D005907:Gliclazide / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D011110:Polymorphism, Genetic
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D005907:Gliclazide