CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers

摘要

Objective: To evaluate the impact of single-nucleotide polymorphisms (SNPs) in CYP2C9, MDR1, SLCO1B1 and ABCG2 on the pharmacokinetics of fluvastatin in Chinese participants. Methods: A pharmacokinetic study of fluvastatin (single dose 40mg) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of fluvastatin were determined by a high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by non-compartmental method. The SNPs were determined by TaqMan ?(MGB) genotyping assay. Results: Effect of CYP2C9*3 (c.1075AC) on area under the plasma concentration-time curve (AUC) of fluvastatin was statistically significant. Heterozygous variant (C/A) carriers had higher AUC values compared to homozygous wild type (A/A) carriers (922.03±148.17g·h·L1 vs. 496.00±168. 93g·h·L1, P=0.003092). The elimination half-life (T 1/2) values of fluvastatin were longer in MDR1 2677non-G carriers than in MDR1 2677G carriers (2.21±0.47h vs. 1.25±0.62h, P=0.02319), and also they were longer in MDR1 1236T-2677non-G-3435T carriers than in MDR1 1236C-2677G-3435C carriers (2.31±0.51h vs. 1.32±0.62h, P=0.03320). MDR1 C3435T polymorphism had a significant effect on maximal plasma concentrations (C max) of fluvastatin. Mutation gene T (TT+CT) carriers had higher C max values compared to homozygous wild type (C/C) carriers (688.54±142.67g·L1 vs. 413.78±177.83g·L1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34GA, ABCG2 c.421CA, SLCO1B1 c.388 AG, SLCO1B1 c.521 TC, SLCO1B1 c.571 TC and SLCO1B1 c.597 CT have no significant effects on fluvastatin pharmacokinetics. Conclusion: CYP2C9*3(1075AC), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.