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...

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Published inActa 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
LanguageEnglish
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
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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 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.
AbstractList 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.
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.AIMCYP2C9 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.METHODSThe 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 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.RESULTSThe 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.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.CONCLUSIONThe 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.
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 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. 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.
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 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. 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.
Author Kang, Byung-sung
Park, Hyun-joo
Jang, Choon-gon
Kim, Bo-hye
Oh, Da-hee
Bae, Jung-woo
Ha, Ji-hey
Lee, Seok-yong
Choi, Chang-ik
Keum, Seul-ki
Na, Han-sung
Chung, Myeon-woo
Park, Jung-in
Bang, Hye-kyoung
Shin, Hee-jung
Oh, Sung-gon
Kim, Mi-jeong
Kim, Young-hoon
Kim, Hae-deun
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  organization: School of Pharmacy, Sungkyunkwan University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/21841812$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright CPS and SIMM 2011
Copyright Nature Publishing Group Oct 2011
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Issue 10
Keywords pharmacokinetics
CYP2C9
Korean
losartan
allele
genotype
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These authors contributed equally to this work.
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Snippet Aim: CYP2C9 enzyme metabolizes numerous clinically important drugs. The aim of this study is to investigate the frequencies of CYP2C9 genotypes and the effects...
CYP2C9 enzyme metabolizes numerous clinically important drugs. The aim of this study is to investigate the frequencies of CYP2C9 genotypes and the effects of...
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StartPage 1303
SubjectTerms 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
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Title Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics
URI https://link.springer.com/article/10.1038/aps.2011.100
https://www.ncbi.nlm.nih.gov/pubmed/21841812
https://www.proquest.com/docview/896279959
https://www.proquest.com/docview/896527386
https://pubmed.ncbi.nlm.nih.gov/PMC4010224
Volume 32
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