氯吡格雷抵抗的临床基因多态性研究进展

孙月梅, 崔明霞, 李文斌, 张娟红, 陈玉艳, 鹿辉, 王昌, 王荣

中国药学杂志 ›› 2018, Vol. 53 ›› Issue (18) : 1529-1535.

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中国药学杂志 ›› 2018, Vol. 53 ›› Issue (18) : 1529-1535. DOI: 10.11669/cpj.2018.18.001
综述

氯吡格雷抵抗的临床基因多态性研究进展

  • 孙月梅1,2, 崔明霞1*, 李文斌2, 张娟红2, 陈玉艳2, 鹿辉2, 王昌2, 王荣1,2*
作者信息 +

Research Progress on Clinical Gene Polymorphism of Clopidogrel Resistance

  • SUN Yue-mei1,2, CUI Ming-xia1*, LI Wen-bin2, ZHANG Juan-hong2, CHEN Yu-yan2, LU Hui2, WANG Chang2, WANG Rong1,2*
Author information +
文章历史 +

摘要

氯吡格雷作为抗血小板聚集药物,尤其在急性冠状动脉综合征、经皮冠状动脉介入术后治疗时发挥重要作用。然而在临床给药过程中发现,易出现氯吡格雷抵抗。参与氯吡格雷反应抵抗的因素很多,目前的关注点主要集中在CYP450酶基因多态性与氯吡格雷抵抗的研究,有关转运体和受体结合位点基因多态性的综述较少,更少见高原人群、不同民族人群间的基因多态性研究。本研究主要从药物吸收转运体的基因多态性与氯吡格雷生物利用度的关系,药物代谢酶对氯吡格雷的生物转化,氯吡格雷活性代谢产物与受体结合发挥药效的全过程进行综述,吸收转运体ABCB1基因位点突变会影响氯吡格雷的生物利用度;代谢酶基因多态性中起关键作用的是CYP2C19和CES1,应根据基因分型调整剂量;生物学活性基因P2Y12基因多态性会影响氯吡格雷的疗效。因此,掌握氯吡格雷基因多态性的影响因素,有助于氯吡格雷的个体化给药,以最大限度地减少抗血小板效应不足导致的血栓性事件或抗血小板效应过度导致的出血性事件。

Abstract

Clopidogrel plays an important role in anti-platelet aggregation, especially in acute coronary syndrome and percutaneous coronary intervention. However, clopidogrel resistance is common in clinical treatment. There are many factors response to clopidogrel resistance.Current researches concentrated in CYP450 enzyme gene polymorphism with clopidogrel resistance. There are few reviews on genetic polymorphisms of transporter and receptor binding sites, furthermore, the gene polymorphisms among different ethnic groups in plateau populations are very rare. In this paper, we mainly reviewed the relationship between gene polymorphism of drug-transporter and bioavailability of clopidogrel, the whole process of drug-metabolizing enzyme′s bioconversion of clopidogrel and the active metabolite of clopidogrel combine with the receptors.A mutation in the ABCB1 gene of the transporter was found to affect the bioavailability of clopidogrel. The key role of polymorphisms in the metabolic enzyme gene is CYP2C19 and CES1. The dose should be adjusted according to genotyping. The biologically active gene P2Y12 polymorphism affects the efficacy of clopidogrel. Therefore, understanding the clopidogrel gene polymorphism influencing factors can help individualized administration of clopidogrel to minimize thrombotic events caused by insufficient antiplatelet effect or hemorrhagic events caused by excessive anti-platelet effect .

关键词

氯吡格雷 / 氯吡格雷抵抗 / 基因多态性 / 生物转化 / 个体化给药

Key words

clopidogrel / clopidogrel resistance / gene polymorphism / bioconversion / individualized administration

引用本文

导出引用
孙月梅, 崔明霞, 李文斌, 张娟红, 陈玉艳, 鹿辉, 王昌, 王荣. 氯吡格雷抵抗的临床基因多态性研究进展[J]. 中国药学杂志, 2018, 53(18): 1529-1535 https://doi.org/10.11669/cpj.2018.18.001
SUN Yue-mei, CUI Ming-xia, LI Wen-bin, ZHANG Juan-hong, CHEN Yu-yan, LU Hui, WANG Chang, WANG Rong. Research Progress on Clinical Gene Polymorphism of Clopidogrel Resistance[J]. Chinese Pharmaceutical Journal, 2018, 53(18): 1529-1535 https://doi.org/10.11669/cpj.2018.18.001
中图分类号: R969.1   

参考文献

[1] PERRY C G, SHULDINER A R. Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation?. J Human Genet, 2013, 58(6):339-345.
[2] NGUYEN T A, DIODATI J G, PHARAND C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol, 2005, 45(8):1157-1164.
[3] FORD N F. Clopidogrel resistance: pharmacokinetic or pharmacogenetic?. J Clin Pharm, 2009, 49(5):506-512.
[4] HASAN M S, BASRI H B, HIN L P, et al. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Inter J Neurosci, 2013, 123(3):143-154.
[5] JIANG X L, SAMANT S, LESKO L J, et al. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmaco, 2015, 54(2):147-166.
[6] DANSETTE P M, ROSI J, BERTHO G, et al. Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer. Chem Res Toxicol, 2012, 25(2):348-356.
[7] SAVI P, PEREILLO J M, UZABIAGA M F, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost, 2000, 84(5):891-896.
[8] KAZUI M, NISHIYA Y, ISHIZUKA T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Meta Dispos, 2010, 38(1):92-99.
[9] SILVESTRO L, GHEORGHE M, IORDACHESCU A, et al. Development and validation of an HPLC-MS/MS method to quantify clopidogrel acyl glucuronide, clopidogrel acid metabolite, and clopidogrel in plasma samples avoiding analyte back-conversion. Anal Bioanal Chem, 2011, 401(3):1023-1034.
[10] TANG M, MUKUNDAN M, YANG J, et al. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharm Exper Ther, 2006, 319(3):1467-1476.
[11] HAGIHARA K, KAZUI M, KURIHARA A, et al. A possible mechanism for the differences in efficiency and variability of active metabolite formation from thienopyridine antiplatelet agents, prasugrel and clopidogrel. Drug Meta Dispos, 2009, 37(11):2145-2152.
[12] SHULDINER A R, O′CONNELL J R, BLIDEN K P, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. Jama, 2009, 302(8):849-857.
[13] LI X X, LÜJ N, FAN W. Effect of CYP2C19 gene polymorphism on antiplatelet effect of clopidogrel therapy . Chin J Clin Neurosci(中国临床神经科学), 2016,24(2):225-232.
[14] JR H D, DEHMER G J, KAUL S, et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovas. J Am Coll Cardiol, 2010, 56(4):321-341.
[15] GROS P, BEN NERIAH Y B, CROOP J M, et al. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature, 1986, 323(6090):728-731.
[16] STOKANOVIC D, NIKOLIC V N, KONSTANTINOVIC S S, et al. P-Glycoprotein polymorphism C3435T is associated with dose-adjusted clopidogrel and 2-Oxo-clopidogrel concentration. Pharmacology, 2016, 97(3-4):101-106.
[17] XU L, LI S X. The research progress of clopidogrel individual drug response variability . Med Recapit(医学综述), 2015, 21(24):4515-4517.
[18] SIMON T, VERSTUYFT C, MARYKRAUSE M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. New Engl J Med, 2009, 360(4):363-375.
[19] NAKAMURA T, SAKAEDA T, OHMOTO N, et al. Real-time quantitative polymerase chain reaction for MDR1, MRP1, MRP2, and CYP3A-mRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas. Drug Meta Disposit Bio Fate Chem,2002,30(1):4-6.
[20] MORIYA Y, NAKAMURA T, HORINOUCHI M, et al. Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects. Bio Pharm Bull, 2002, 25(10):1356-1359.
[21] SU J, YU Q, ZHU H, et al. The risk of clopidogrel resistance is associated with ABCB1 polymorphisms but not promoter methylation in a Chinese Han population. PLoS One, 2017, 12(3):e0174511.
[22] XIE X, HOU H J, ZHANG Z Z, et al.Correlation study of gene polymorphism of CYP2C19 and clopidogrel response after percutaneous transluminal angioplasty and stenting in patients with ischemic cerebrovascular disease . J Med Postgra(医学研究生学报), 2015,(12):1298-1302.
[23] MEGA J L, CLOSE S L, WIVIOTT S D, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet, 2010, 376(9749):1312-1319.
[24] JUN-FENG S U, XIAO-HUI H U, CHENG-YAN L I. Risk factors for clopidogrel resistance in patients with ischemic cerebral infarction and the correlation with ABCB1 gene rs1045642 polymorphism. Exper Ther Med, 2015, 9(1):267-271.
[25] ZHAI Y, HE H, MA X, et al. Meta-analysis of effects of ABCB1, polymorphisms on clopidogrel response among patients with coronary artery disease. Eur J Clin Pharmacol, 2017(10):1-12.
[26] LUO M, LI J, XU X, et al. ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a Meta-analysis. Thromb Res, 2012, 129(6):754-759.
[27] KAZUI M, NISHIYA Y, ISHIZUKA T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Meta Dispos, 2010, 38(1):92-99.
[28] ZHAO L,ZHANG X L. Clinical value of CYP2C19 genotype detection in the treatment of acute coronary syndrome with clopidogrel. Chin Pharm J(中国药学杂志), 2012, 47(20):1671-1673.
[29] SCOTT S A, SANGKUHL K, STEIN C M, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther, 2013, 94(3):317-323.
[30] MIZOBE M, HOKIMOTO S, AKASAKA T, et al. Impact of CYP2C19 polymorphism on clinical outcome following coronary stenting is more important in non-diabetic than diabetic patients . Throm Res, 2014, 134(1):72-77.
[31] SUBRAJA K, DKHAR S A, PRIYADHARSINI R, et al. Genetic polymorphisms of CYP2C19, influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilianpopulation. Eur J Clin Pharmacol, 2013, 69(3):415-422.
[32] ZHANG S, LAI X, LI W, et al. VASP phosphorylation and genetic polymorphism for clopidogrel resistance in Chinese patients with non-cardio embolic ischemic stroke. Throm Res, 2014, 134(6):1272-1277.
[33] WEI W, FANG L, WANG N, et al. Prevalence of CYP2C19 polymorphisms involved in clopidogrel metabolism in Fejian Hart populatio. Chin J Med Genet(中华医学遗传学杂志), 2012, 29(4):420-425.
[34] HULOT J S, BURA A, VILLARD E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood, 2006, 108(7):2244-2247.
[35] SAYDAM F, DEIRMENCI Í, BIRDANE A, et al. The CYP2C19*2 and CYP2C19*17 polymorphisms play a vital role in clopidogrel responsiveness after percutaneous coronary intervention: a pharmacogenomics study. Basic Clin Pharmacol Toxicol, 2017, 121(1):29-36.
[36] HU G X, DAI D P, WANG H, et al. Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population. Pharmacogenomics, 2017, 18(4):369-379.
[37] ZANGER U M, SCHWAB M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther, 2013, 138(1):103-141.
[38] NICOLAS J M, ESPIE P, MOLIMARD M. Gender and interindividual variability in pharmacokinetics. Drug Meta Rev, 2008, 41(3):408-421.
[39] WERK A N, CASCORBI I. Functional gene variants of CYP3A4. Clin Pharmacol Ther, 2014, 96(3):340-348.
[40] MCGRAW J, WALLER D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Meta Toxicol, 2012, 8(3):371-382.
[41] AOUAM K, KOLSI A, KERKENI E, et al. Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase. Pharmacogenomics, 2015, 16(18):2045-2054.
[42] WANG D, GUO Y, WRIGHTON S A, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogeno J, 2011, 11(4):274-286.
[43] DANIELAK D, KARAZNIEWICZ-łADA M, WISNIEWSKA K, et al. Impact of CYP3A4*1G, allele on clinical pharmacokinetics and pharmacodynamics of clopidogrel. Eur J Drug Meta Pharmaco, 2016, 42(1):1-9.
[44] LI H,LI M N, KANG P F, et al. Correlation between cytochrome 3A4 + 894C>T P450 gene polymorphism and outcomes of coronary intervention in patients with acute coronary syndrome. J South Med Univ(南方医科大学学报), 2017, 37(2):261-265.
[45] ZHANG D, ZHANG X, DAN L, et al. Association between insulin receptor substrate-1 polymorphisms and high platelet reactivity with clopidogrel therapy in coronary artery disease patients with type 2 diabetes mellitus. Cardiovascular Diabet, 2016, 15(1):1-8.
[46] ZHAO Y Z. Influence of CYP2B6, B4GALT2 Gene Polymorphism and biochemical parameters on the antiplatelet action of clopidogrel in CHD patients . Anhui Med Univ, 2017.
[47] KIRCHHEINER J, BROCKMÖLLER J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther, 2005, 77(1):1-16.
[48] ZHAO F, LOKE C, RANKIN S C, et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther, 2004, 76(3):210-219.
[49] BRANDT J T, CLOSE S L, ITURRIA S J, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Throm Haemost, 2007, 5(12):2429-2436.
[50] GUO Y, JIANG X M. Research progress of PON. Chin Gerontol(中国老年学), 2008, 28(5):518-519.
[51] NISHIO R, SHINKE T, OTAKE H, et al. Paraoxonase-1 activity affects the clopidogrel response in CYP2C19 loss-of-function carriers. Throm Res, 2013, 132(5):558-564.
[52] BOUMAN H J, SCHMÖMIG E, VAN WERKUM J W, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med, 2011, 17(1):110-116.
[53] ZHAO Y Z,XU D J,LI J. Meta-analysis of the effect of PON1 Q192R gene polymorphism on clinical efficacy of clopidogrel in Chinese patients with coronary heart disease . Chin J Clin Pharm Ther(中国临床药理学与治疗学), 2016, 21(9):1018-1023.
[54] CHAN M Y, TAN K, TAN H C, et al. CYP2C19 and PON1 polymorphisms regulating clopidogrelbioactivation in Chinese, Malay and Indian subjects. Pharmacogenomics, 2012, 13(5):533-542.
[55] HOSOKAWA M. Structure and catalytic properties of carboxylesteraseisozymes involved in metabolic activation of prodrugs. Molecules, 2008, 13(2):412-431.
[56] SHI D, YANG D, PRINSSEN E P, et al. Surge in expression of carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza prodrug oseltamivir. J Infect Dis, 2011, 203(7):937-942.
[57] TARKIAINEN E K, BACKMAN J T, NEUVONEN M, et al. Carboxylesterase 1 polymorphism impairs oseltamivir bioactivation in humans. Clin Pharmacol Ther, 2012, 92(1):68-71.
[58] LEWIS J P, HORENSTEIN R B, RYAN K, et al. The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenetics Genomics, 2013, 23(1):1-8.
[59] XIAO F Y, LUO J Q, LIU M, et al. Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients. Sci Rep, 2017, 7(1):7244.
[60] ANGIOLILLO D J, FERNANDEZORTIZ A, BERNARDO E, et al. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease.. Throm Res, 2005, 116(6):491-497.
[61] IDRISSI H H, HMIMECH W, KHORB N E, et al. Does i-T744C P2Y12 polymorphism modulate clopidogrel response among moroccan acute coronary syndromes patients?. Genet Res Int,2017, 2017(24):1-7.
[62] CUISSET T, FRERE C, QUILICI J, et al. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome. Throm Res, 2007, 120(6):893-899.
[63] HETHERINGTON S L, SINGH R K, LODWICK D, et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscl Throm Vas Bio, 2005, 25(1):252-257.
[64] KIMCHI-SARFATY C,OH J M,KIM I W, et al. A“silent”polymorphismin the MDR1 gene changes substrate specificity. Science,2007,315(5811): 525-528.
[65] WEI Q,ZHONG C,LI B. Research progress of high altitude pulmonary edema . Chin J Lab Diagn(中国实验诊断学), 2016, 20(4):694-697.
[66] LI W B, LUO B F, WANG R, et al. Changes of P-gp expression in rats’ small intestine and effects on uptake of levofloxacin after acute exposure to hypoxia. Acta Pharm Sin(药学学报), 2016, 51(9):1412-1416.
[67] SUN Y H. The effect of acute lung injury on rat liver injury and its effect on CYP450 enzyme . Lanzhou:University of Lanzhou, 2015.
[68] GUO Z Q, JIA Z P, MA J, et al. Genetic polymorphism analysis of cytochrome P450 2C19 in Chinese Hui and Zang populations of Gansu . Pract Pharm Clin Remed(实用药物与临床), 2010, 13(2):95-97.

基金

国家自然科学基金项目资助(81403004, 81673508,81401552);全军后勤科研“十二五”重大项目资助(AWS14L0005);国家科技重大专项资助项目(2008ZXJ09014-010);全军医学科研"十二五"重点项目资助(BWS12J012);甘肃省自然基金项目资助(145RJZA111,1606RJZA176);兰州大学中央高校基本科研业务费专项资金项目资助(lzujbky-2017-141)
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