Portal de Periódicos da CAPES

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

2011; Springer Nature; Volume: 32; Issue: 10 Linguagem: Inglês

10.1038/aps.2011.100

1745-7254

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,

Drug-Induced Hepatotoxicity and Protection

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. 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. 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 AUC0–∞ of losartan in CYP2C9*3/*3 subjects was 1.42-fold larger than that in CYP2C9*1/*1 subjects, and the AUC0–∞ of E-3174, a more active metabolite of losartan, in CYP2C9*3/*3 subjects was only 12% of that in CYP2C9*1/*1 subjects. 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.