title: Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects.
abstract: 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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dayong
authors.initials: D
authors.lastname: Si
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guo
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
mesh_terms: 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
chemical_list: 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