Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics

Jung Woo Bae, Chang Ik Choi, Mi Jeong Kim, Da Hee Oh, Seul Ki Keum, Jung In Park, Bo Hye Kim, Hye Kyoung Bang, Sung Gon Oh, Byung Sung Kang, Hyun Joo Park, Hae Deun Kim, Ji Hey Ha, Hee Jung Shin, Young Hoon Kim, Han Sung Na, Myeon Woo Chung, Choon Gon Jang, Seok Yong Lee

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40 Scopus citations

Abstract

Aim: CYP2C9 enzyme metabolizes numerous clinically important drugs. The aim of this study is to investigate the frequencies of CYP2C9 genotypes and the effects of selected alleles on losartan pharmacokinetics in a large sample of the Korean population. Methods: The CYP2C9 gene was genotyped in 1796 healthy Korean subjects. CYP2C9 alleles (CYP2C9*1, *2, *3, and *13 alleles) were measured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and direct sequencing assay. The enzymatic activity of each CYP2C9 genotype was evaluated using losartan as the substrate. Results: The frequencies of CYP2C9*1, *3, and *13 allele were 0.952 (95% confidence interval 0.945.0.959), 0.044 (95% CI 0.037. 0.051), and 0.005 (95% CI 0.003.0.007), respectively. The frequencies of the CYP2C9*1/*1, *1/*3, *1/*13, and *3/*3 genotypes were 0.904 (95% CI 0.890.0.918), 0.085 (95% CI 0.072.0.098), 0.009 (95% CI 0.005.0.013), and 0.001 (95% CI 0.000.0.002), respectively. In the pharmacokinetics studies, the AUC 0.∞ of losartan in CYP2C9*3/*3 subject was 1.42-fold larger than that in CYP2C9*1/*1 subjects, and the AUC 0.∞ of E-3174, a more active metabolite of losartan, in CYP2C9*3/*3 subject was only 12% of that in CYP2C9*1/*1 subjects. Conclusion: The results confirmed the frequencies of CYP2C9 genotypes in a large cohort of Koreans, and detected the CYP2C9*3/*3 genotype. CYP2C9*3/*3 subjects metabolized much less losartan into E-3174 than CYP2C9*1/*1 subjects.

Original languageEnglish
Pages (from-to)1303-1308
Number of pages6
JournalActa Pharmacologica Sinica
Volume32
Issue number10
DOIs
StatePublished - Oct 2011

Keywords

  • allele
  • CYP2C9
  • genotype
  • Korean
  • losartan
  • pharmacokinetics

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