Background and Objective: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Methods: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Results: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 ± 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 ± 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 ± 61.9 ng · h/mL for CYP3A5*1 carriers and 167.6 ± 45.0 ng · h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 ± 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 ± 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. Conclusions: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.
ASJC Scopus subject areas