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ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421c > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics.
Pharmazie. 2013 Feb; 68(2):129-34.P

Abstract

A randomized cross-over pharmacokinetic study of rosuvastatin calcium (single dose: 5 mg, 10 mg and 20 mg; multiple doses: 10mg 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, SLCOB1, 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 (Cav,ss) and area under the plasma concentration versus time curve during the dosing interval at steady state (AUCss)], dose-normalized (based on 5 mg) pharmacokinetic parameters of single-dose rosuvastatin were further analyzed. Rosuvastatin exhibited linear pharmacokinetics and great inter-subject variability. Cav,ss, AUCss and dose-normalized peak plasma concentration (Cmax) and AUC(0-infinity) 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 Cav,ss, AUCss, Cmax and AUC(0-infinity) (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 Cmax (11.16 +/- 3.10 microg x L(-1) vs 8.35 +/- 3.31 microg x L(-1), p < 0.05) and AUC(0-infinity) (86.61 +/- 24.32 microg x h x L(-1) vs 62.60 +/- 26.19 microg x h x 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 Cmax (12.20 +/- 4.09 microg x L(-1) vs 8.70 +/- 3.09 microg x L(-1), p < 0.05) and AUC(0-infinity) (98.74 +/- 25.36 microg x h x L(-1) vs 64.97 +/- 24.90 microg x h x L(-1), p < 0.05) values compared to heterozygotes (CA) and homozygotes (CC) carriers. There were no significant effects on single-dose and steady-state pharmacokinetics of rosuvastatin by CYP2C9*3 (1075A > 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.

Authors+Show Affiliations

Department of Pharmacy, the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23469685

Citation

Zhou, Quan, et al. "ABCB1 Gene Polymorphisms, ABCB1 Haplotypes and ABCG2 C.421c > a Are Determinants of Inter-subject Variability in Rosuvastatin Pharmacokinetics." Die Pharmazie, vol. 68, no. 2, 2013, pp. 129-34.
Zhou Q, Ruan ZR, Yuan H, et al. ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421c > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics. Pharmazie. 2013;68(2):129-34.
Zhou, Q., Ruan, Z. R., Yuan, H., Xu, D. H., & Zeng, S. (2013). ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421c > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics. Die Pharmazie, 68(2), 129-34.
Zhou Q, et al. ABCB1 Gene Polymorphisms, ABCB1 Haplotypes and ABCG2 C.421c > a Are Determinants of Inter-subject Variability in Rosuvastatin Pharmacokinetics. Pharmazie. 2013;68(2):129-34. PubMed PMID: 23469685.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421c > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics. AU - Zhou,Quan, AU - Ruan,Zou-Rong, AU - Yuan,Hong, AU - Xu,Dong-Hang, AU - Zeng,Su, PY - 2013/3/9/entrez PY - 2013/3/9/pubmed PY - 2013/4/9/medline SP - 129 EP - 34 JF - Die Pharmazie JO - Pharmazie VL - 68 IS - 2 N2 - A randomized cross-over pharmacokinetic study of rosuvastatin calcium (single dose: 5 mg, 10 mg and 20 mg; multiple doses: 10mg 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, SLCOB1, 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 (Cav,ss) and area under the plasma concentration versus time curve during the dosing interval at steady state (AUCss)], dose-normalized (based on 5 mg) pharmacokinetic parameters of single-dose rosuvastatin were further analyzed. Rosuvastatin exhibited linear pharmacokinetics and great inter-subject variability. Cav,ss, AUCss and dose-normalized peak plasma concentration (Cmax) and AUC(0-infinity) 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 Cav,ss, AUCss, Cmax and AUC(0-infinity) (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 Cmax (11.16 +/- 3.10 microg x L(-1) vs 8.35 +/- 3.31 microg x L(-1), p < 0.05) and AUC(0-infinity) (86.61 +/- 24.32 microg x h x L(-1) vs 62.60 +/- 26.19 microg x h x 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 Cmax (12.20 +/- 4.09 microg x L(-1) vs 8.70 +/- 3.09 microg x L(-1), p < 0.05) and AUC(0-infinity) (98.74 +/- 25.36 microg x h x L(-1) vs 64.97 +/- 24.90 microg x h x L(-1), p < 0.05) values compared to heterozygotes (CA) and homozygotes (CC) carriers. There were no significant effects on single-dose and steady-state pharmacokinetics of rosuvastatin by CYP2C9*3 (1075A > 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. SN - 0031-7144 UR - https://www.unboundmedicine.com/medline/citation/23469685/ABCB1_gene_polymorphisms_ABCB1_haplotypes_and_ABCG2_c_421c_>_A_are_determinants_of_inter_subject_variability_in_rosuvastatin_pharmacokinetics_ L2 - https://medlineplus.gov/cholesterolmedicines.html DB - PRIME DP - Unbound Medicine ER -