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

Kyoung Ah Kim, Pil Whan Park, Ock Je Lee, Sang Hyun Choi, Bon Hong Min, Kyung Ho Shin, Boe Gwun Chun, Jae Gook Shin, Ji Young Park

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    58 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)646-656
    Number of pages11
    JournalClinical Pharmacology and Therapeutics
    Volume80
    Issue number6
    DOIs
    Publication statusPublished - 2006 Dec

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)

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