CYP2C9 genetic polymorphism significantly affected the pharmacokinetics of candesartan and its metabolite

Purpose: Candesartan cilexetil, a selective nonpeptide angiotensin II receptor subtype 1 antagonist, is primarily used in the treatment of hypertension. During gastrointestinal absorption, candesartan cilexetil is converted into its active metabolite, candesartan. Candesartan is further metabolized to the inactive compound MII, mediate by CYP2C9 enzymes. We investigated the effects of CYP2C9 genetic variants on the pharmacokinetics of candesartan and its metabolite.

Methods: Twenty-two subjects were selected and they were divided into two different groups according to CYP2C9 genotype, CYP2C9EM (CYP2C9*1/*1, n=12) and CYP2C9IM (CYP2C19*1/*3 or CYP2C19*1/*13, n=10). After overnight fasting, each subject received a single oral dose of 16 mg candesartan cilexetil. Blood samples were collected up to 36 hr after drug intake, and the plasma concentrations of candesartan and its metabolites were determined by using HPLC system with fluorescence detection.

Results: AUC_inf of candesartan in CYP2C9IM group was 1.3-fold higher than that in CYP2C9EM group (P<0.01). Apparent oral clearance of candesartan in CYP2C9IM group was 27% lower than that in CYP2C9EM group (P<0.01). C_max and AUC_inf of MII were also significantly different between two genotype groups (all P<0.01). AUC ratio of MII over candesartan was significantly decreased in CYP2C9IM group (1.31 ± 0.26) compared to CYP2C9EM group (2.50 ± 0.53, P<0.0001).

Conclusion: CYP2C9 genetic polymorphism reduced the metabolism of candesartan into its inactive metabolite.