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Effect of Polymorphic CYP3A5 Genotype on the Single-Dose Simvastatin Pharmacokinetics in Healthy Subjects

From the Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul (Dr Kim, Mr Lee, Mr Kang, Dr J-Y Park), and the Department of Laboratory Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea (Dr P-W Park).

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.

Key Words: Cytochrome P450 3A5 (CYP3A5)/ • simvastatin • pharmacokinetics • pharmacogenetics • CYP3A5^*3

Address for reprints: Ji-Young Park, MD, PhD, Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Sungbuk-gu, Seoul 136-705, Korea.

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