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

• Published in: Acta pharmacologica Sinica Vol. 32; no. 10; pp. 1303 - 1308
• Main Authors: Bae, Jung-woo, Choi, Chang-ik, Kim, Mi-jeong, Oh, Da-hee, Keum, Seul-ki, Park, Jung-in, Kim, Bo-hye, Bang, Hye-kyoung, Oh, Sung-gon, Kang, Byung-sung, Park, Hyun-joo, Kim, Hae-deun, Ha, Ji-hey, Shin, Hee-jung, Kim, Young-hoon, Na, Han-sung, Chung, Myeon-woo, Jang, Choon-gon, Lee, Seok-yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2011; Nature Publishing Group
• Subjects: Adult; Alleles; Antihypertensive Agents - blood; Aryl Hydrocarbon Hydroxylases - genetics; Asian Continental Ancestry Group - genetics; Biomedical and Life Sciences; Biomedicine; Cytochrome P-450 CYP2C9; Gene Frequency; Genotype; Humans; Imidazoles - blood; Immunology; Internal Medicine; Losartan - blood; Male; Medical Microbiology; Original; original-article; Pharmacology/Toxicology; Tetrazoles - blood; Vaccine; Young Adult; pharmacokinetics; CYP2C9; Korean; losartan; allele; genotype
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/aps.2011.100

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 subjects 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 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.