CYP2C93 and 13 alleles significantly affect the pharmacokinetics of irbesartan in healthy Korean subjects

• Published in: European journal of clinical pharmacology Vol. 68; no. 2; pp. 149 - 154
• Main Authors: Choi, Chang-Ik, Kim, Mi-Jeong, Chung, Eun-Kyung, Lee, Hye-In, Jang, Choon-Gon, Bae, Jung-Woo, Lee, Seok-Yong
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2012; Springer; Springer Nature B.V
• Subjects: Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Genetics; Health; Kinetics; Medical sciences; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Asia; Korea; CYP2C9; Irbesartan; Pharmacokinetics; Genetic polymorphism; Imidazole derivatives; Tetrazole derivatives; Genetic variability; Isozyme; Peptide hormone; Octapeptide; Genetics; Angiotensin II; Human; Healthy subject; Enzyme; Cytochrome P450; Genotype; Genetic polymorphisms; Renin angiotensin system; Allele; Biphenyl derivatives; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; CYP2C9 gene; Polymorphism
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-011-1098-0

Purpose To evaluate the effects of two major polymorphisms of CYP2C9 , CYP2C9*3 and CYP2C9*13 , on the pharmacokinetics of irbesartan in healthy Korean volunteers. Methods A single 150-mg oral dose of irbesartan was given to 28 Korean volunteers, who had different CYP2C9 genotypes (12, 10, and 6 carriers of CYP2C9*1/*1 , *1/*3 , and *1/*13 genotypes respectively). Irbesartan levels were analyzed using HPLC fluorescence in plasma samples collected up to 36 h after the drug intake. Results Compared with CYP2C9*1 homozygous subjects, not only were the maximum plasma concentrations (C max ) of irbesartan in CYP2C9*1/*3 and *1/*13 subjects 1.56- and 1.50-fold higher ( P  = 0.001), but the half-lives were also 1.38- and 1.50-fold longer ( P  = 0.001). The area under the plasma concentration–time curve (AUC) was 1.64- and 1.79-fold higher ( P  < 0.001). The oral clearance of irbesartan was 39.3% and 44.0% lower in the CYP2C9*1/*3 and *1/*13 subjects respectively, than in the *1/*1 subjects ( P  < 0.001). Likewise, the increases in half-life and decreases in oral clearance observed in CYP2C9*1/*13 individuals were similar to those in participants expressing the CYP2C9*1/*3 genotype. Conclusions CYP2C9 genetic polymorphisms markedly affected the pharmacokinetics of irbesartan in this study sample. The CYP2C9*3 and CYP2C9*13 alleles appear to be associated with the decreased metabolism of irbesartan.