Study on genetic factors of clopidogrel resistance

Abstract

Abstract: Clopidogrel is an antiplatelet drug, which has been confirmed as one of the standard treatments for the prevention of stent thrombosis in coronary heart disease(CHD). However, ischemic events still occur in population under routine dosage of clopidogrel treatment, which may due to the variabilities of platelet response to clopidogrel. This phenomenon is defined as clopidogrel resistance(CR). The mechanism of CR has not been clearly elucidated yet, gene polymorphism is considered as one of the most important reasons. In this review, we will discuss the impact of genetic variations of transportors, drug metabolizing enzymes and receptors in pharmacokinetic, pharmacodynamic and clinical responses to clopidogrel.

Key words: Clopidogrel resistance, Gene polymorphism, Cytochrome P450

CLC Number:

R969

HE Chun-hui, HU Qin , ZOU Jian-jun, CHEN Shao-liang, FAN Hong-wei, XIE Hong-guang, ZHU Yu-bing. Study on genetic factors of clopidogrel resistance[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(11): 1288-1293.

References

[1] Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial[J]. Lancet, 2008, 371(9621): 1353-1363.
[2] Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation[J]. N Engl J Med,2005, 352(12): 1179-1189.
[3] Sugunaraj JP, Palaniswamy C, Selvaraj DR, et al. Clopidogrel resistance[J]. Am J Ther, 2010, 17(2): 210-215.
[4] Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence[J]. J Am Coll Cardiol, 2005, 45(8): 1157-1164.
[5] O'Donnell CJ, Larson MG, Feng D, et al. Genetic and environmental contributions to platelet aggregation, the Framingham heart study[J]. Circulation, 200l, 103(25): 3051-3056.
[6] Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events[J]. N Engl J Med , 2009, 360(4): 363-375.
[7] Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity[J]. Circulation, 2003, 107(23): 2908-2913.
[8] Guisset T, Frere C, Quilici J, et al. Role of the T744c polymorphism of tlle P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome [J]. Thromb Res,2007, 120(6) : 893-899.
[9] Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse prospective study[J]. J Am Coll Cardiol, 2008, 51(14): 1404-1411.
[10] CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) [J]. Lancet, 1996, 348(9038): 1329-1339.
[11] Michelson AD, Frelinger AL 3rd, Furman MI. Current options in platelet function testing[J]. Am J Cardiol , 2006, 98(10A): 4N-10N.
[12] 余长永,张勇,邹建军,等.氯吡格雷抵抗原因及对策的研究进展[J].中国临床药理学与治疗学,2009,14(10):1168-1173.
[13] Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs[J]. Nature, 2001, 409(6817):202-207.
[14] Taubert D, Von Beckerath N, Grimberg G, et al. Impact of P-glycoprotein on clopidogrel absorption[J]. Clin Pharmacol Ther, 2006, 80(5): 486-501.
[15] Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin[J]. Drug Meatb Disops, 2002, 31(1): 53-59.
[16] Ma TK, Lam YY, Tan VP, et al. Impact of genetic and acquired alteration in cytochrome P450 system on pharmacologic and clinical response to clopidogrel[J]. Pharmacol Ther, 2010, 125(2): 249-259.
[17] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel[J]. Arterioscler Thromb Vasc Biol, 2006, 26(8): 1895-1900.
[18] Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance[J]. Circulation, 2004, 109(2): 166-171.
[19] Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function ploymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C ploymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients[J]. Pharmacogenet Genomics, 2007, 17(12): 1057-1064.
[20] Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet, 2001, 27(4): 383-391.
[21] Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polym idogrel[J]. CMAJ, 2006, 147(12): 1715-1722.
[22] Smith SM, Judge HM, Peters G, et al. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy[J]. Platelets, 2006, 17(4): 250-258.
[23] Kim KA, Park PW, Park JY. Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects[J]. Eur J Clin Pharmacol, 2008, 64(6): 589-597.
[24] Xie H, Griskevicius L, Stahle L, et al. Pharmacogenetics of cyclophosphamide in patients with hematological malignancies[J]. Eur J Pharm Sci, 2006, 27(1): 54-61.
[25] Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents[J]. J Am Coll Cardiol, 2008, 51(20): 1925-1934.
[26] Brandt JT, Close SL, Iturria SJ, et al. Commons polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel[J]. J Thromb Haemost, 2007, 5(12): 2429-2436.
[27] Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel[J]. N Engl J Med ,2009, 360(4): 354-362.
[28] Lee JM, Park S, Shin DJ, et al. Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans[J]. Am J Cardiol, 2009, 104(1): 46-51.
[29] Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19^*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement[J]. Circulation, 2010, 121(4): 512-518.
[30] Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregationis associated with P2Y12 gene sequence variations in healthy subjects[J]. Circulation, 2003, 108(8) : 989 - 995.
[31] Cuisset T, Frere C, Quilici J, et al. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome[J]. Thromb Res, 2007, 120(6): 893-899.
[32] 陈碧莲,李清,解勤之,等.P2Y12受体基因多态性在中国人群中的分布和对氯吡格雷疗效的影响[J].中国新药杂志,2008,17(16):1435-1439.
[33] Weiss EJ, Bray PF, Tayback M, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis[J]. N Engl J Med, 1996, 334(17): 1090-1094.
[34] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. PlA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation[J].Blood Coagul Fibrinolysis, 2004, 15(1): 89-93.
[35] Lev EI, Patel RT, Gut hikonda S, et al. Genetic polymorphisms of the platelet receptors P2Y12, P2Y1 and GPⅢa and response to aspirin and clopidogrel[J]. Thromb Res, 2007, 119(3): 355-360.