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