CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are Determinants of Inter-subject Variability in Fluvastatin Pharmacokinetics in Healthy Chinese Volunteers

被引：15
作者：
Zhou, Q. [1 ]
Ruan, Z. -r. [2 ]
Yuan, H. [2 ]
Zeng, S. [3 ]
机构：
[1] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Pharm, Hangzhou, Zhejiang, Peoples R China
[2] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Div Clin Pharmacol, Hangzhou, Zhejiang, Peoples R China
[3] Zhejiang Univ, Coll Pharmaceut Sci, Dept Pharmaceut Anal & Drug Metab, Hangzhou 310058, Zhejiang, Peoples R China
来源：
ARZNEIMITTELFORSCHUNG-DRUG RESEARCH | 2012年 / 62卷 / 11期
基金：
中国国家自然科学基金;
关键词：
fluvastatin; pharmacokinetics; single-nucleotide polymorphism; cytochrome p450; drug transporter; SLCO1B1; POLYMORPHISM; ASSOCIATION; PRAVASTATIN; ROSUVASTATIN; TRANSPORTER; HAPLOTYPES; DRUGS;
D O I：
10.1055/s-0032-1323696
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
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 40 mg) 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 (R)(MGB) genotyping assay. Results: Effect of CYP2C9*3 (c.1075A>C) 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 +/- 148.17 mu g.h.L-1 vs. 496.00 +/- 168.93 mu g.h.L-1, 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 +/- 0.47 h vs. 1.25 +/- 0.62 h, 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 0435T 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 +/- 142.67 mu g.L-1 vs. . 413.78 +/- 177.83 mu g.L-1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34G>A, ABCG2 c.421C>A, SLCO1B1 c.388 A>G, SLCO1B1 c.521 T>C, SLCO1B1 c.571 T>C and SLCO1B1 c.597 C>T have no significant effects on fluvastatin pharmacokinetics. Conclusion: CYP2C9*3(1075A>C), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.
引用
收藏
页码：519 / 524
页数：6
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