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

Abstract

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^®(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 µg · h · L^− 1 vs. 496.00±168.93 µg · 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±0.51 h vs. 1.32±0.62 h, 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±142.67 µg · L^− 1 vs. . 413.78±177.83 µg · 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.

Key words

fluvastatin - pharmacokinetics - single-nucleotide polymorphism - cytochrome p450 - drug transporter

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