-
他汀类药物抑制胆固醇合成途径的限速酶3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMG-CoA还原酶)的活性,抑制胆固醇的生成,上调肝细胞表面的LDL受体以加快LDL的分解代谢。阿托伐他汀以活性酸形式给药,通过被动扩散或OATP1B1转运进入肝细胞,主要由CYP3A4在肝脏和肠壁代谢阿托伐他汀,少量由CYP2C9、CYP2C19、CYP3A5和UGT1A1代谢。阿托伐他汀酸由CYP3A代谢产生邻、对位羟基活性代谢产物,在体内它们与各自的非活性内酯形式处于平衡状态。ABCB1(编码p-gp)和ABCG2(编码BCRP)介导阿托伐他汀及其代谢物从肝脏排入胆汁后消除(图1)[1]。
HTML
[1] | KESKITALO J E, ZOLK O, FROMM M F, et al. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin[J]. Clin Pharmacol Ther,2009,86(2):197-203. |
[2] | KAJINAMI K, TAKEKOSHI N, BROUSSEAU M E, et al. Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management[J]. Atherosclerosis,2004,177(2):219-234. |
[3] | HE B X, SHI L, QIU J, et al. The effect of CYP3A4*1G allele on the pharmacokinetics of atorvastatin in Chinese Han patients with coronary heart disease[J]. J Clin Pharmacol,2014,54(4):462-467. |
[4] | GAO Y, ZHANG L R, FU Q. CYP3A4*1G polymorphism is associated with lipid-lowering efficacy of atorvastatin but not of simvastatin[J]. Eur J Clin Pharmacol,2008,64(9):877-882. |
[5] | WANG D, GUO Y, WRIGHTON S A, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs[J]. Pharmacogenomics J,2011,11(4):274-286. |
[6] | BECKER M L, VISSER L E, VAN SCHAIK R H, et al. Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy[J]. Pharmacoepidemiol Drug Saf,2010,19(1):75-81. |
[7] | KAJINAMI K, BROUSSEAU M E, ORDOVAS J M, et al. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia[J]. Am J Cardiol,2004,93(1):104-107. |
[8] | ROSALES A, ALVEAR M, CUEVAS A, et al. Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia[J]. Clinica Chimica Acta,2012,413(3-4):495-501. |
[9] | KIVISTÖ K T, NIEMI M, SCHAEFFELER E, et al. Lipid-lowering response to statins is affected by CYP3A5 polymorphism[J]. Pharmacogenetics,2004,14(8):523-525. |
[10] | PENG C, DING Y, YI X, et al. Polymorphisms in CYP450 genes and the therapeutic effect of atorvastatin on ischemic stroke: a retrospective cohort study in Chinese population[J]. Clin Ther,2018,40(3):469-477.e2. |
[11] | CHO S K, OH E S, PARK K, et al. The UGT1A3*2 polymorphism affects atorvastatin lactonization and lipid-lowering effect in healthy volunteers[J]. Pharmacogenetics Genom,2012,22(8):598-605. |
[12] | STORMO C, BOGSRUD M P, HERMANN M, et al. UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone[J]. Mol Diagn Ther,2013,17(4):233-237. |
[13] | BIRMINGHAM B K, BUJAC S R, ELSBY R, et al. Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect? Eur J Clin Pharmacol,2015,71(3):341-355. |
[14] | PASANEN M K, FREDRIKSON H, NEUVONEN P J, et al. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin[J]. Clin Pharmacol Ther,2007,82(6):726-733. |
[15] | WANG Y, TIAN Y, LV P, et al. The effect of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Chinese people[J]. Die Pharmazie,2017,72(6):365-368. |
[16] | 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 Genomics,2005,15(7):513-522. |
[17] | PETERS B J M, RODIN A S, KLUNGEL O H, et al. Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction[J]. Pharmacogenomics,2010,11(8):1065-1076. |
[18] | PRADO Y, SAAVEDRA N, ZAMBRANO T, et al. SLCO1B1 c. 388A>G polymorphism is associated with HDL-C levels in response to atorvastatin in Chilean individuals[J]. Int J Mol Sci,2015,16(9):20609-20619. |
[19] | GRADHAND U, KIM R B. Pharmacogenomics of mrp transporters (ABCC1-5) and bcrp (ABCG2)[J]. Drug Metab Rev,2008,40(2):317-354. |
[20] | TSAMANDOURAS N, GUO Y Y, WENDLING T, et al. Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population[J]. Pharmacogenetics Genom,2017,27(1):27-38. |
[21] | KESKITALO J E, KURKINEN K J, NEUVONEN P J, et al. ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin[J]. Clin Pharmacol Ther,2008,84(4):457-461. |
[22] | PODURI A, KHULLAR M, BAHL A, et al. Common variants of HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy[J]. DNA Cell Biol,2010,29(10):629-637. |
[23] | KAJINAMI K, BROUSSEAU M E, ORDOVAS J M, et al. Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender-specific manner[J]. Am J Cardiol,2004,93(8):1046-1050. |
[24] | RODRIGUES A C, REBECCHI I M M, BERTOLAMI M C, et al. High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent[J]. Braz J Med Biol Res,2005,38(9):1389-1397. |
[25] | DEGORTER M K, TIRONA R G, SCHWARZ U I, et al. Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care[J]. Circ Cardiovasc Genet,2013,6(4):400-408. |
[26] | JOHNSON J M, CASTLE J, GARRETT-ENGELE P, et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays[J]. Science,2003,302(5653):2141-2144. |
[27] | MEDINA M W, KRAUSS R M. The role of HMGCR alternative splicing in statin efficacy[J]. Trends Cardiovasc Med,2009,19(5):173-177. |
[28] | YU C Y, THEUSCH E, LO K, et al. HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism[J]. Hum Mol Genet,2014,23(2):319-332. |
[29] | LEDUC V, BOURQUE L, POIRIER J, et al. Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia[J]. Pharmacogenet Genomics,2016,26(1):1-11. |
[30] | CUEVAS A, FERNÁNDEZ C, FERRADA L, et al. HMGCR rs17671591 SNP determines lower plasma LDL-C after atorvastatin therapy in Chilean individuals[J]. Basic Clin Pharmacol Toxicol,2016,118(4):292-297. |
[31] | PEDRO-BOTET J, SCHAEFER E J, BAKKER-ARKEMA R G, et al. Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner[J]. Atherosclerosis,2001,158(1):183-193. |
[32] | CERDA A, GENVIGIR F D, WILLRICH M A, et al. Apolipoprotein E mRNA expression in mononuclear cells from normolipidemic and hypercholesterolemic individuals treated with atorvastatin[J]. Lipids Health Dis,2011,10:206. |
[33] | DESHMUKH H A, COLHOUN H M, JOHNSON T, et al. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)[J]. J Lipid Res,2012,53(5):1000-1011. |
[34] | LAGOS J, ZAMBRANO T, ROSALES A, et al. APOE polymorphisms contribute to reduced atorvastatin response in Chilean Amerindian subjects[J]. Int J Mol Sci,2015,16(4):7890-7899. |
[35] | JIANG X Y, ZHANG Q, CHEN P, et al. CYP7A1 polymorphism influences the LDL cholesterol-lowering response to atorvastatin[J]. J Clin Pharm Ther,2012,37(6):719-723. |
[36] | KAJINAMI K, BROUSSEAU M E, NARTSUPHA C, et al. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin[J]. J Lipid Res,2004,45(4):653-656. |
[37] | KAJINAMI K, BROUSSEAU M E, ORDOVAS J M, et al. Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin[J]. Atherosclerosis,2004,175(2):287-293. |
[38] | GU G L, XU X L, YANG Q Y, et al. Effect of CETP polymorphism on atorvastatin lipid-regulating effect and clinical prognosis of patients with coronary heart disease[J]. Med Sci Monit,2014,20:2824-2829. |
[39] | STROES E S, THOMPSON P D, CORSINI A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management[J]. Eur Heart J,2015,36(17):1012-1022. |
[40] | BRUCKERT E, HAYEM G, DEJAGER S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the PRIMO study[J]. Cardiovasc Drugs Ther,2005,19(6):403-414. |
[41] | DU Y M, WANG S Z, CHEN Z Y, et al. Association of SLCO1B1 polymorphisms and atorvastatin safety and efficacy: a meta-analysis[J]. Curr Pharm Des,2019,24(34):4044-4050. |
[42] | BRUNHAM L R, LANSBERG P J, ZHANG L, et al. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin[J]. Pharmacogenomics J,2012,12(3):233-237. |
[43] | MIROŠEVIĆ SKVRCE N, MACOLIĆ ŠARINIĆ V, ŠIMIĆ I, et al. ABCG2 gene polymorphisms as risk factors for atorvastatin adverse reactions: a case–control study[J]. Pharmacogenomics,2015,16(8):803-815. |
[44] | LIU J E, LIU X Y, CHEN S, et al. SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study[J]. Eur J Clin Pharmacol,2017,73(11):1409-1416. |
[45] | WILKE R A, MOORE J H, BURMESTER J K. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage[J]. Pharmacogenetics Genom,2005,15(6):415-421. |
[46] | CHATZIZISIS Y S, KOSKINAS K C, MISIRLI G, et al. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment[J]. Drug Saf,2010,33(3):171-187. |
[47] | FUKUNAGA K, NAKAGAWA H, ISHIKAWA T, et al. ABCB1 polymorphism is associated with atorvastatin-induced liver injury in Japanese population[J]. BMC Genet,2016,17(1):79. |