瑞苏伐他汀遗传药理学研究进展

摘要/Abstract

摘要： 胆固醇水平升高是动脉粥样硬化发病的主要原因。瑞苏伐他汀为临床常用的抑制胆固醇合成的药物,其药动学和药效学存在显著个体差异。药物转运体、药物代谢酶、药物靶点的遗传多态性对瑞苏伐他汀的体内代谢和临床疗效个体差异具有重要作用。本文阐述了药物转运体、细胞色素P450酶和其他相关基因的遗传多态性对瑞苏伐他汀药动学和药效学的影响,为临床制定个体化用药方案提供参考。

关键词: 动脉粥样硬化, 瑞苏伐他汀, 遗传药理学, 转运体

Abstract: Hypercholesterolemia plays a key role in the initiation and progression of atherosclerosis. Rosuvastatin is widely used to prevent cholesterol synthesis. There are great individual differences in pharmacokinetics and pharmacodynamics characters in clinical use of rosuvastatin.Pharmacogenetics indicates that genetic polymorphisms of drug transporters, metabolizing enzymes, and receptors play very important roles in the metabolism and therapeutical efficacy of rosuvastatin. In this review, we summarized the effects of genetic polymorphisms of certain drug transporters, CYP450 enzymes or other related genes on the pharmacokinetics and pharmacodynamics of rosuvastatin.It will provide part of the basis for personalized medicine of rosuvastatin.

Key words: Atherosclerosis, Rosuvastatin, Pharmacogenetics, Transporter

中图分类号:

R968

鲍美华, 张轶雯, 程琳, 周宏灏. 瑞苏伐他汀遗传药理学研究进展[J]. 中国临床药理学与治疗学, 2013, 18(2): 234-240.

BAO Mei-hua, ZHANG Yi-wen, CHENG Lin, ZHOU Hong-hao. Pharmacogenetic progress of rosuvastatin in atherosclerosis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(2): 234-240.

参考文献

[1] Ridker PM, Danielson E, Fonseca FA, et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein[J].N Engl J Med, 2008, 359(21):2195-2207.
[2] Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor[J]. Cardiovasc Drug Rev, 2002, 20(4): 303-328.
[3] 杨娟,李禄金,何迎春,等. 瑞舒伐他汀钙治疗中国高脂血症人群的药效动力学探索[J]. 中国临床药理学与治疗学,2012,15(8):894-900.
[4] Mangravite LM, Krauss RM.Pharmacogenomics of statin response[J]. Curr Opin Lipidol, 2007,18(7):409-414.
[5] Sekino H, Onishi T.Phase I study of ZD4522 (rosuvastatin), a new HMG-CoA reductase inhibitor-evaluation of tolerance and pharmacokinetics in healthy adult male volunteers after single and repeated oral administration[J]. J Clin Ther Med, 2005, 21(2):187-203.
[6] Lee E, Ryan S, Birmingham B, et al.Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment[J]. Clin Pharmacol Ther, 2005, 78(4):330-341.
[7] Tzeng T, Mitchell P, Zhang H, et al. Population pharmacokinetics of rosuvastatin in normal subjects and subjects with dyslipidemia [J]. Clin Pharmacol Ther, 2004, 75:56(PII-18)
[8] Buckett L, Ballard P, Davidson R, et al. Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versus non-hepatic cells [J].Atherosclerosis, 2000, 151(1) : 41(MoP29:W6).
[9] Martin PD, Warwick MJ, Dane AL, et al.Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers[J]. Clin Ther, 2003, 25(10):2553-2563.
[10] Kameyama Y, Yamashita K, Kobayashi K, et al.Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells[J]. Pharmacogenet Genom,2005,15(7):513-522.
[11] 张伟,贺毅憬,周宏灏. 有机阴离子转运多肽1B1的遗传药理学进展[J]. 中国临床药理学与治疗学,2008,13(7):721-729.
[12] Niemi M.High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C SLCO1B1)[J]. Pharmacogenetics, 2004,14(7):429-440.
[13] Kim RB.3-Hydroxy-3-methylglutaryl- coenzyme A reductase inhibitors (statins) and genetic variability (single nucleotide polymorphisms) in a hepatic drug uptake transporter: what's it all about[J] ?Clin Pharmacol Ther, 2004,75(5):381-385.
[14] Pasanen MK, Fredrikson H, Neuvonen PJ, et al.Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin[J]. Clin Pharmacol & Ther, 2007, 82(6):726-733.
[15] Choi JH, Lee MG, Cho JY, et al.Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans[J]. Clin Pharmacol Ther, 2008,83(2):251-257.
[16] 隋双明, 温金华, 李新华,等. OATP1B1 基因位点521T→C 的突变对瑞舒伐他汀在中国健康人体内药代动力学特征的影响[J]. 药学学报, 2011,46(6):695-700.
[17] Pasanen MK, Miettinen TA, Gylling H, et al.Polymorphism of the hepatic influx transporter organic anion transporting polypeptide 1B1 is associated with increased cholesterol synthesis rate[J]. Pharmacogenet Genom,2008, 18(10):921-926.
[18] Zamber CP, Lamba JK, Yasuda K, et al.Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine[J].Pharmacogenetics, 2003,13(1):19-28.
[19] Hirano M, Maeda K, Matsushima S, et al.Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin[J]. Mol Pharmacol, 2005, 68(3):800-807.
[20] Itoda M, Saito Y, Shirao K, et al.Eight novel single nucleotide polymorphisms in ABCG2/BCRP in Japanese cancer patients administered irinotecan[J]. Drug Metab Pharmacok, 2003,18(3):212-217.
[21] Zhang W, Yu BN, He YJ, et al.Role of BCRP 421C>A polymorphism on rosuvastatin pharmaco- kinetics in healthy Chinese males[J]. Clin Chim Acta, 2006,373(1/2):99-103.
[22] Keskitalo JE, Zolk O, Fromm MF, et al.ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin[J]. Clin Pharmacol Ther, 2009, 86(2):197-203.
[23] Hu M, To KK, Mak VW, et al.The ABCG2 transporter and its relations with the pharmacokinetics, drug interaction and lipid-lowering effects of statins[J]. Expert Opin Drug Met, 2011,7(1):49-62.
[24] Tomlinson B, Hu M, Lee VW, et al.ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin[J]. Clin Pharmacol Ther, 2010, 87(5):558-562.
[25] Fromm MF.Importance of P-glycoprotein at blood-tissue barriers[J]. Trends Pharmacol Sci, 2004,25(8):423-429.
[26] Kim RB,Wandel C, Leake B, et al.Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein[J]. Pharm Res, 1999,16(3):408-414.
[27] Chen C, Mireles RJ, Campbell SD, et al.Differential interaction of 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitors with ABCB1, ABCC2, and OATP1B1[J]. Drug Metab Dispos, 2005,33(4):537-546.
[28] Matsushima S, Maeda K, Kondo C, et al.Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein[J]. J Pharmacol Exp Ther, 2005,314(3):1059-1067.
[29] Kitamura S, Maeda K, Wang Y, et al.Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin[J]. Drug Metab Dispos, 2008,36(10):2014-2023.
[30] Bercovich D, Friedlander Y, Korem S, et al.The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia[J]. Atherosclerosis, 2006, 185(1):97-107.
[31] Jenni EK, Kaisa JK, Mikko N, et al.No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin[J]. Br J Clin Pharmacol, 2009,68(2):207-213.
[32] Ridker PM, MacFadyen JG, Glynn RJ, et al. Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of rosuvastatin in primary prevention[J]. Circ Cardiovasc Genet, 2011, 4(3):312-317.
[33] 许文燊, 鄢盛恺, 杨辉,等. KIF6基因rs20455多态性与中国北方汉族人冠心病及血脂水平的关联研究[J]. 中国分子心脏病学杂志, 2011, 11(6):352-354.
[34] Bailey KM, Romaine SP, Jackson BM, et al.Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study[J]. Circ Cardiovasc Genet, 2010, 3(3):276-285.
[35] Chen XP, Du GH.Lectin-like oxidized low-density lipoprotein receptor-1: protein, ligands, expression and pathophysiological significance[J]. Chinese Medical Journal, 2007, 120(5):421-426
[36] Mango R, Biocca S, Vecchio FD, et al.In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction[J]. Circ Res, 2005, 97(2):152-158.
[37] Chen Q, Reis SE, Kammerer C, et al.Genetic variation in lectin-like low-density lipoprotein receptor 1(LOX-1) gene and the risk of coronary artery disease[J]. Circulation, 2011,107: 3146-3150.
[38] Puccetti L, Pasqui AL, Pastorelli M, et al.3'UTR/T polymorphism of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with modifed anti-platelet activity of atorvastatin in hypercholesterolemic subjects[J]. Atherosclerosis, 2005,183(2):322-332.
[39] Puccetti L, Santilli F, Pasqui AL, et al.Effects of atorvastatin and rosuvastatin on thromboxane- dependent platelet activation and oxidative stress in hypercholesterolemia[J]. Atherosclerosis, 2011, 214(1):122-128.
[40] Hu M, Lui SS, Mak VW, et al.Pharmacogenetic analysis of lipid responses to rosuvastatin in Chinese patients[J]. Pharmacogenet Genomics, 2010,20(10):634-637.
[41] Pan W, Song IS, Shin HJ, et al.Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations[J]. Xenobiotica, 2011,41(6):501-510.
[42] Chien KL, Wang KC, Chen YC, et al.Common sequence variants in pharmacodynamic and pharmacokinetic pathway-related genes conferring LDL cholesterol response to statins[J]. Pharmacogenomics, 2010,11(3):309-317.