title: Frequency of CYP2C9 variant alleles, including CYP2C9*13 in a Korean population and effect on glimepiride pharmacokinetics.
abstract: OBJECTIVE
  Cytochrome P450 (CYP) 2C9 is a clinically important enzyme involved in the metabolism of many drugs commonly used in humans. Of several allelic variants known to affect the catalytic activity of the CYP2C9 enzyme, the frequencies of the CYP2C9*3 and CYP2C9*13 alleles in the Korean population have been reported as 1·1% and 0·6%, respectively. Our objective was to re-evaluate the frequencies of CYP2C9 allelic variants in the Korean population, including the CYP2C9*13 allele by pyrosequencing, and to investigate the pharmacokinetics of glimepiride in relation to CYP2C9 genotypes, including CYP2C9*3/*3.
  
  
  METHODS
  295 subjects were genotyped for CYP2C9*2 and CYP2C9*3 using the TaqMan procedure, and for CYP2C9*13 using pyrosequencing. These data were combined with our previously reported data to assess the CYP2C9 allele and genotype frequencies in 869 Korean subjects. Data from 24 of the 295 genotyped subjects (22 CYP2C9*1/*1 homozygotes, one CYP2C9*1/*3 heterozygote and one CYP2C9*3/*3 homozygote) who had participated in a bioequivalence study were analysed retrospectively to examine the effects of CYP2C9 genotype on glimepiride pharmacokinetics.
  
  
  RESULTS
  The frequencies of the CYP2C9*1/*3, *3/*3, and *1/*13 genotypes in the study population (n = 295) were 0·081 (n = 24), 0·010 (n = 3) and 0·003 (n = 1), respectively. In the 869 subjects from the combined studies, allele frequencies for CYP2C9*3 and CYP2C9*13 were 0·025 (95% CI: 0·018, 0·033) and 0·002 (95% CI: 0·000, 0·010), respectively. Relative to CYP2C9*1 homozygotes, the one CYP2C9*3 homozygous subject was found to have a higher AUC(0-∞) value (490% of the reference value) and a lower oral clearance rate (18% of the reference).
  
  
  CONCLUSIONS
  This study is the first examination of CYP2C9*3 homozygotes in the Korean population. Our data on the one subject with this genotype suggest that CYP2C9*3/*3 momozygotes have lower clearance of glimepiride and are exposed to higher levels of the drug than wild-type homozygotes. Although we identified a subject with the CYP2C9*13 allele using a new pyrosequencing assay, we were unfortunately unable to investigate its effects on glimepiride pharmacokinetics.
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Lee
authors.forename: M-s
authors.initials: MS
authors.lastname: Lim
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: M-Y
authors.initials: MY
authors.lastname: Jegal
authors.forename: D-W
authors.initials: DW
authors.lastname: Kim
authors.forename: W-K
authors.initials: WK
authors.lastname: Lee
authors.forename: I-J
authors.initials: IJ
authors.lastname: Jang
authors.forename: J-G
authors.initials: JG
authors.lastname: Shin
authors.forename: Y-R
authors.initials: YR
authors.lastname: Yoon
mesh_terms: D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D011110:Polymorphism, Genetic; D056910:Republic of Korea; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D013453:Sulfonylurea Compounds / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases