Effect of Cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Kyoung Ah Kim, Pil Whan Park, Ji Young Park

    Research output: Contribution to journalArticlepeer-review

    10 Citations (Scopus)

    Abstract

    Amlodipine is a racemic mixture composed of S- and R-form and metabolized stereoselectively. Cytochrome P450 3A (CYP3A) including CYP3A5 are involved in the metabolism of amlodipine and it was reported that polymorphic CYP3A5 genotype modulates the plasma levels of amlodipine and thus affect its pharmacokinetics. This study was conducted to find whether stereoselective pharmacokinetics of amlodipine was affected by the polymorphic CYP3A5 genotype. Seventeen healthy subjects were genotyped for CYP3A5*3 variant. After a single dose of 10-mg amlodipine, enantiomers of amlodipine were analyzed using HPLC-MS/MS equipped with an AGP column. Amlodipine showed stereoselective pharmacokinetics. S-amlodipine exhibited higher plasma levels than R-amlodipine in both genotype groups. S-amlodipine showed 15% higher mean peak plasma concentrations (Cmax) in CYP3A5*1/ *3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P 5 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P 5 0.114). CYP3A5*1/*3 carriers also have 23 and 12% higher mean area under the time versus concentration curve of R-amlodipine and S-amlodipine than CYP3A5*3/*3 carriers, respectively (for R-amlodipine, 147.1 ng*h/ml for CYP3A5*1/*3 carriers versus 121.8 ng*h/ml for CYP3A5*3/*3 carriers, P 5 0.234; for S-amlodipine, 161.6 ng*h/ml for CYP3A5*1/*3 carriers vs. 144.2 ng*h/ml for CYP3A5*3/*3 carriers, P 5 0.353). Other pharmacokinetic parameters also showed no significant difference between them. In conclusion, the present study showed that despite the evidence that amlodipine is stereoselectively metabolized, CYP3A5*3 genotype did not affect stereoselective disposition of amlodipine. It provides the evidence that CYP3A5*3-genotype plays a minor role in the interindividual variability of stereoselective disposition of amlodipine in humans.

    Original languageEnglish
    Pages (from-to)485-491
    Number of pages7
    JournalChirality
    Volume21
    Issue number5
    DOIs
    Publication statusPublished - 2009

    Keywords

    • Amlodipine
    • CYP3A5*3
    • Cytochrome P450 3A5
    • Stereoselectivity

    ASJC Scopus subject areas

    • Analytical Chemistry
    • Catalysis
    • Pharmacology
    • Drug Discovery
    • Spectroscopy
    • Organic Chemistry

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