title: Simvastatin pharmacokinetics in healthy Chinese subjects and its relations with CYP2C9, CYP3A5, ABCB1, ABCG2 and SLCO1B1 polymorphisms.
abstract: A pharmacokinetic study of simvastatin (single oral dose, 40 mg) was conducted in 17 healthy Chinese volunteers. Plasma concentrations of simvastatin were determined by an LC-ESI-MS-MS method. The pharmacokinetic parameters of simvastatin were derived with a non-compartmental method. The polymorphisms of CYP2C9, CYP3A5, ABCB1 (encoding P-gp), ABCG2 (encoding BCRP) and SLCO1B1 (encoding OATP1B1) were determined by TaqMan genotyping assay and the impacts of these SNPs on the pharmacokinetics of simvastatin were analyzed. Major pharmacokinetic parameters were as follows: Tmax 1.44 +/- 0.39 h, Cmax 9.83 +/- 2.41 microg x L(-1), t1/2 4.85 +/- 1.23 h and AUC(0-infinity) 40.32 +/- 6.82 microg x h x L(-1). Effect of ABCB1 G2677T/A SNP on dispostion of simvastatin was observed. Significant differences in t1/2, but not Cmax and AUC(0-infinity), were observed between G/A, G/T or G/G carriers and non-G carriers (5.65 +/- 0.50 h vs 4.41 +/- 1.31 h, P < 0.05). There were no significant effects on simvastatin pharmacokinetics by SNPs such as CYP2C9*3 (1075A > C), CYP3A5*3 g.6986A > G, ABCB1 C3435T, ABCG2 c.34G > A, ABCG2 c.421C>A, SLCO1B1 c.388 A > G, SLCO1B1 c.521 T > C, SLCO1B1 g.11187 G > A, SLCO1B1 c.571 T > C and SLCO1B1 c.597 C > T. We conclude here that there is a small inter-subject variation in simvastatin pharmacokinetics in healthy Chinese volunteers. P-gp, OATP1 B1 and BCRP seem unlikely to play an important role in the pharmacokinetics of simvastatin. The gene-dose effects of ABCG2 c.421 C > A and CYP3A5*3 g.6986A > G on simvastatin pharmacokinetics are not strong enough in Chinese subjects.
authors.affiliation: Department of Pharmacy, the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Zou-Rong
authors.initials: ZR
authors.lastname: Ruan
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007202:Indicators and Reagents; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D019821:Simvastatin / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D019821:Simvastatin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A