Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects

• Published in: Journal of clinical pharmacology Vol. 47; no. 1; p. 87
• Main Authors: Kim, Kyoung-Ah, Park, Pil-Whan, Lee, Ock-Je, Kang, Dong-Kyun, Park, Ji-Young
• Format: Journal Article
• Language: English
• Published: England 01.01.2007
• Subjects: Administration, Oral; Adult; Analysis of Variance; Area Under Curve; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; DNA Primers; Genotype; Half-Life; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - blood; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Sequence Analysis, DNA; Simvastatin - administration & dosage; Simvastatin - blood; Simvastatin - pharmacokinetics; Time Factors
• ISSN: 0091-2700
• DOI: 10.1177/0091270006295063

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 x h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 +/- 6.37 ng x 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.