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

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 CYP2C91/*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 CYP2C93/3 subjects was 1.42-fold larger than that in CYP2C91/1 subjects, and the AUC(0-∞) of E-3174, a more active metabolite of losartan, in CYP2C93/3 subjects was only 12% of that in CYP2C91/*1 subjects.

CONCLUSION

The results confirmed the frequencies of CYP2C9 genotypes in a large cohort of Koreans, and detected the CYP2C9*3/3 genotype. CYP2C93/3 subjects metabolized much less losartan into E-3174 than CYP2C91/*1 subjects.