Effects of the polymorphic MDR1 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects / 대한내과학회지

ABSTRACT

BACKGROUND/AIMS: Simvastatin has dramatically reduced cardiovascular disease due to elevated cholesterol. The human multidrug resistance 1 gene (MDR1) encodes a 170-kDa transmembrane glycoprotein (P-glycoprotein), which plays an important role in regulating the absorption, distribution, and excretion of simvastatin. To clarify the effects of the MDR1 gene polymorphism on simvastatin pharmacokinetics, we investigated whether there is an association between genotype and the pharmacokinetic parameters for simvastatin. METHODS: Thirty-one healthy unrelated Korean volunteers were genotyped for MDR1. Genomic DNA from blood was analyzed using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Following an overnight fast, all of the subjects took a single 60-mg oral dose of simvastatin. Venous blood samples were taken for 12 hours after the oral drug intake. A statistical analysis of the MDR1 genotype and pharmacokinetic parameters of simvastatin was performed. RESULTS: The mean Tmax of the 1236TT genotype was significantly higher than that of CT and CC (p=0.02). The mean AUC0-12h of 3435TT was also significantly higher, compared with CT and CC (p=0.01). No significant difference was observed between the MDR1 single nucleotide polymorphism (SNP) for G2677A/T and the pharmacokinetic parameters. CONCLUSIONS: These findings suggest that polymorphic MDR1 genes are important in the inter-individual variation of the disposition of simvastatin in humans. s