Abstract
Simvastatin reduces plasma cholesterol by inhibiting HMG-CoA reductase (HMGR) and is widely used in the treatment of hypercholesterolemia. To screening the possible genetic factors affecting the pharmacokinetics (PK) of simvastatin, 35 male Korean volunteers were enrolled from two separate bioequivalence studies. Each subject was administered 20 mg simvastatin and reference drug PK parameters were used. We used Illumina Human610Quad v1.0 DNA Analysis BeadChip for whole genome SNPs analysis and whole genome genotyping data was processed by linear regression analysis for PK parameters of drug metabolizing enzymes and transporters. We found 145 significant SNPs (P < 0.01) in Cmax, 135 significant SNPs (P < 0.01) in Tmax and 85 significant SNPs (P < 0.01) in AUCinf from whole genome analysis. In particular, we found that the ABCC2 gene had a significant effect on Cmax and AUCinf. These results could provide information of possible candidate genes for personalized simvastatin therapy.
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Table 1.
Demographic characteristics and reference simvastatin pharmacokinetics parameters of volunteers
Abbreviation; M: male, F: female, Cmax: maximum measured plasma concentration, Tmax: time of the maximum measured plasma concentration, AUCt: area under the plasma concentration-time curve from time zero to time of last measurable concentration, AUCinf: area under the plasma concentration-time curve from zero to infinity, SD: standard deviation.
Table 2.
Summary of linear regression analysis
Table 3.
Highly significant SNPs of drug metabolizing enzymes in Cmax group from linear regression analysis
Table 4.
Highly significant SNPs of drug-metabolizing enzymes in Tmax group from linear regression analysis
Table 5.
Highly significant SNPs of drug-metabolizing enzymes in AUCinf group from linear regression analysis