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 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.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Although this was confirmed by other investigators in Caucasian (Lee et al, 2003a,b) and Japanese subjects (Sekino et al, 2003), it was proposed that tolbutamide may be a superior probe for this polymorphism compared with losartan (Lee et al, 2003a). The importance of genotype at the CYP2C9 locus for conversion of losartan to EXP3174 was also confirmed in a study of almost 1800 Korean subjects (Bae et al, 2011). In a smaller Korean study, CYP*1/*3 and *1/*13 similarly reduced EXP3174 generation but were not different from each other .…”

Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast

“…In our previous reports (Bae et al 2005(Bae et al , 2011b, we found only two subjects with the Each value represents the mean ± SD, except t max given as the median (range None of the individuals were identified as having the CYP2C9*3/*13 or CYP2C9*13/*13 genotypes. We were not able to obtain the data from PMs because none of the PMs whom we found consented to participation in this study.…”

“…The observed frequency of the CYP2C9*13 is ranged from 0.2 to 1.0 %, and is found only in Asian populations, including Koreans (Si et al 2004;Bae et al 2005Bae et al , 2011bLi et al 2009;Maekawa et al 2009;Scott et al 2011). Thus, we were able to recruit only three subjects with the CYP2C9*1/*13 genotype in the present study.…”

“…The CYP2C9*2 and CYP2C9*3 alleles are common in Caucasians, in whom the frequencies range from 8.0 to 19.1 % and 3.3 to 16.2 %, respectively (García-Martín et al 2006). CYP2C9*2 allele is rarely observed in Asian populations, while the frequency of CYP2C9*3 allele ranges from 0.07 to 6.0 % (Bae et al 2005;2011b;Nakai et al 2005;García-Martín et al 2006). The CYP2C9*13, a unique allele identified only in Asian populations, has been detected in Chinese, Japanese, and Korean samples with low frequencies of 0.2-1.0 % (Si et al 2004;Bae et al 2005;2011b;Li et al 2009;Maekawa et al 2009).…”

Effect of CYP2C9*3 mutant variants on meloxicam pharmacokinetics in a healthy Chinese population

“…In mammals, meloxicam is mainly converted to a 5-hydroxymethyl metabolite by the enzyme CYP2C9 (Schmid et al, 1995;Chesne et al, 1998). Thirty-five different types of CYP2C9 alleles have been reported to date (http://www.cypalleles.ki.se/cyp2c9.htm), of which CYP2C9*2 and CYP2C9*3 were the most frequently identified in most populations (Bae et al, 2011a). Individuals with CYP2C9 variant genotypes may not metabolize drugs adequately, resulting in changes in drug toxicity.…”