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Effect of Polymorphic CYP3A5 Genotype on the Single‐Dose Simvastatin Pharmacokinetics in Healthy Subjects
Author(s) -
Kim KyoungAh,
Park PilWhan,
Lee OckJe,
Kang DongKyun,
Park JiYoung
Publication year - 2007
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270006295063
Subject(s) - simvastatin , pharmacokinetics , cyp3a5 , pharmacology , genotype , medicine , cyp3a4 , dosing , chemistry , endocrinology , metabolism , biochemistry , cytochrome p450 , gene
Simvastatin, a cholesterol‐lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty‐two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20‐mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (±SD) area under the plasma concentration‐time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 ± 2.25 ng • h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 ± 6.37 ng • h/mL; P = .013, Bonferroni test). The mean (±SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 ± 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 ± 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half‐life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.