ABCB1 Gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421C > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics

A randomized cross-over pharmacokinetic study of rosuvastatin calcium (single dose: 5 mg, 10 mg and 20 mg; multiple doses: 10 mg once daily for 7 days) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of rosuvastatin were determined by an LC-ESI-MS-MS method. Single-nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLCO1B1, CYP2C9 and CYP3A5 were determined by TaqMan® (MGB) genotyping assay. An impact of the aforementioned SNPs on steady state pharmacokinetic parameters [average steady state concentration (C av,ss) and area under the plasma concentration versus time curve during the dosing interval at steady state (AUC ss)], dose-normalized (based on 5 mg) pharmacokinetic parameters of single-dose rosuvastatin were further analyzed. Rosuvastatin exhibited linear pharmacokinetics and great inter-subject variability. C av,ss, AUC ss and dose-normalized peak plasma concentration (C max) and AUC (0-∞) of single-dose rosuvastatin were significantly related with ABCB1 C1236T, G2677T/A and C3435T polymorphisms and ABCB1 haplotypes. Compared to homozygous wild type and heterozygous mutation gene carriers, subjects carrying the variant ABCB1 1236TT, 2677 non-G or 3435TT genotype had higher C av,ss, AUC ss, C max and AUC (0-∞) (p<0.05). ABCB1 haplotype (1236TT-2677TT-3435TT) had significant influence on dose-normalized pharmacokinetics of single-dose rosuvastatin. ABCB1 haplotype (1236TT-2677TT-3435TT) carriers (n = 12) had obvious higher C max (11.16 ± 3.10 μg·L–1 vs 8.35 ± 3.31 μg·L–1, p<0.05) and AUC (0-∞) (86.61 ± 24.32 μg·h·L–1 vs 62.60 ± 26.19 μg·h·L–1, p<0.05) compared to non-1236TT-2677TT-3435TT carriers (n = 24). ABCG2 c.421C > A had a significant impact on rosuvastatin pharmacokinetics. Homozygotes (AA) carriers had obvious higher C max (12.20 ± 4.09 μg·L–1 vs 8.70 ± 3.09 μg·L–1, p<0.05) and AUC (0-∞) (98.74 ± 25.36 μg·h·L–1 vs 64.97 ± 24.90 μg·h·L–1, p C), CYP3A5*3 g.6986A > G, ABCG2 c.34G > A, SLCO1B1 c.521 T > C, c.388 A > G, g.11187 G > A, c.571 T > C and c.597 C > T. In addition, no difference in rosuvastatin pharmacokinetics was observed among subjects of different genders. We conclude that ABCB1 C1236T, G2677T/A and C3435T polymorphism, ABCB1 haplotypes and ABCG2 c.421C > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics in healthy Chinese volunteers, and potentially affect the efficacy and toxicity of statin therapy.