Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects.

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 CYP3A53/3 carriers and 16 were CYP3A51 carriers (CYP3A51/1 in 2 and CYP3A51/3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A51 carriers (27.0 +/- 8.2 L/h) showing 20% lower clearance than CYP3A53/3 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 CYP3A51 carriers and 167.6 +/- 45.0 ng . h/mL for CYP3A53/3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A51 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 CYP3A51 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.