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.