Pharmacogenomics and Personalized Medicine of the Antiplatelet Drugs



Platelet activation and aggregation play a critical role in hemostasis and thrombosis. There is a fast-growing list of the antiplatelet drugs that are either marketed or under development, of which combination of aspirin and clopidogrel is now the standard of care for acute coronary syndromes or percutaneous coronary intervention for stenting. Overwhelming data have well demonstrated that aspirin monotherapy can greatly improve patient outcomes by irreversible suppression of the cyclooxygenase-1 enzyme responsible for the arachidonic acid pathway, that clopidogrel can exert its well-documented platelet inhibition through irreversible blockade of the platelet ADP receptor P2Y12, and that dual antiplatelet therapy (aspirin plus clopidogrel) is clinically more effective than either of the two for the secondary prevention of the recurrence of myocardial infarction, in-stent thrombosis, ischemic stroke, or even death. However, individuals may vary in their response to the drug, characterized by less or no response to either one or both in some patients when taking the same doses. It is well known that almost all genetic and nongenetic factors may contribute to that variation as summarized in this book chapter, and that DNA or pharmacogenomics is not the whole story about personalized medicine. The future landscape of optimal drug therapy would be much clearer over time and thus more attractive.


Platelet Aggregation Stent Thrombosis Grapefruit Juice Platelet Reactivity Antiplatelet Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by a starting research grant No. 31010300010339, funded by the Nanjing First Hospital, Nanjing Medical University, China; a grant No. BK 2012525, funded by the Jiangsu Natural Science Foundation (JSNSF), China; and a starting research grant (No. 2012–258), funded by the Ministry of Human Resources and Social Security, China.


  1. Abernethy DR (1997) Grapefruits and drugs: when is statistically significant clinically significant? J Clin Invest 99:2297–2298PubMedCentralPubMedGoogle Scholar
  2. Adedoyin A, Arns PA, Richards WO, Wilkinson GR, Branch RA (1998) Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 64:8–17PubMedGoogle Scholar
  3. Afshar-Kharghan V, Li CQ, Khoshnevis-Asl M, Lopez JA (1999) Kozak sequence polymorphism of the glycoprotein (GP) Ibalpha gene is a major determinant of the plasma membrane levels of the platelet GP Ib-IX-V complex. Blood 94:186–191PubMedGoogle Scholar
  4. Ajzenberg N, Berroeta C, Philip I, Grandchamp B, Ducellier P, Huart V et al (2005) Association of the -92C/G and 807C/T polymorphisms of the alpha2 subunit gene with human platelets alpha2beta1 receptor density. Arterioscler Thromb Vasc Biol 25:1756–1760PubMedGoogle Scholar
  5. Aleil B, Leon C, Cazenave JP, Gachet C (2009) CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring. J Thromb Haemost 7:1747–1749PubMedGoogle Scholar
  6. Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A et al (2001) MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11:217–221PubMedGoogle Scholar
  7. Ancrenaz V, Desmeules J, James R, Fontana P, Reny JL, Dayer P et al (2012) The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro. Br J Pharmacol 166:2362–2370PubMedCentralPubMedGoogle Scholar
  8. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr et al (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 116:e148–e304PubMedGoogle Scholar
  9. Angiolillo DJ (2012) The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs 72:2087–2116PubMedGoogle Scholar
  10. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Sabate M, Fernandez C et al (2004a) PlA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation. Blood Coagul Fibrinolysis 15:89–93PubMedGoogle Scholar
  11. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Escaned J, Moreno R et al (2004b) 807 C/T Polymorphism of the glycoprotein Ia gene and pharmacogenetic modulation of platelet response to dual antiplatelet treatment. Blood Coagul Fibrinolysis 15:427–433PubMedGoogle Scholar
  12. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Barrera-Ramirez C, Sabate M et al (2005a) Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 115:101–108PubMedGoogle Scholar
  13. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E et al (2005b) Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res 116:491–497PubMedGoogle Scholar
  14. Angiolillo DJ, Bernardo E, Ramirez C, Costa MA, Sabate M, Jimenez-Quevedo P et al (2006a) Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 48:298–304PubMedGoogle Scholar
  15. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E et al (2006b) Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 26:1895–1900PubMedGoogle Scholar
  16. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA et al (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516PubMedGoogle Scholar
  17. Anonymous (2010a) FDA drug safety communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Available at:
  18. Anonymous (2010b) Grapefruit-drug interactions. Available at:
  19. Anonymous (2010c) Plavix prescribing information. Available at:
  20. Ansara AJ, Nisly SA, Arif SA, Koehler JM, Nordmeyer ST (2010) Aspirin dosing for the prevention and treatment of ischemic stroke: an indication-specific review of the literature. Ann Pharmacother 44:851–862PubMedGoogle Scholar
  21. Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK et al (2008a) 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 117:296–329PubMedGoogle Scholar
  22. Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK et al (2008b) 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 51:210–247PubMedGoogle Scholar
  23. Armstrong PC, Peter K (2012) GPIIb/IIIa inhibitors: from bench to bedside and back to bench again. Thromb Haemost 107:808–814PubMedGoogle Scholar
  24. Aukrust P, Halvorsen B, Ueland T, Michelsen AE, Skjelland M, Gullestad L et al (2010) Activated platelets and atherosclerosis. Expert Rev Cardiovasc Ther 8:1297–1307PubMedGoogle Scholar
  25. Badr ER, Lang IM, Koppensteiner R, Calatzis A, Panzer S, Gremmel T (2012) Residual platelet activation through protease-activated receptors (PAR)-1 and −4 in patients on P2Y12 inhibitors. Int J Cardiol doi: 10.1016/j.ijcard.2012.09.103 Google Scholar
  26. Bailey DG, Dresser GK (2004) Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 4:281–297PubMedGoogle Scholar
  27. Balram C, Sharma A, Sivathasan C, Lee EJ (2003) Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population: phenotypic-genotypic correlates. Br J Clin Pharmacol 56:78–83PubMedCentralPubMedGoogle Scholar
  28. Bauer T, Gitt AK, Junger C, Zahn R, Koeth O, Towae F et al (2010) Guideline-recommended secondary prevention drug therapy after acute myocardial infarction: predictors and outcomes of nonadherence. Eur J Cardiovasc Prev Rehabil 17:576–581PubMedGoogle Scholar
  29. Bergandi L, Cordero M, Anselmino M, Ferraro G, Ravera L, Dalmasso P et al (2010) Altered nitric oxide/cGMP platelet signaling pathway in platelets from patients with acute coronary syndromes. Clin Res Cardiol 99:557–564PubMedGoogle Scholar
  30. Bernlochner I, Steinhubl S, Braun S, Morath T, Jaitner J, Stegherr J et al (2010) Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment. Thromb Haemost 104:1193–1200PubMedGoogle Scholar
  31. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH (2000) Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 102:624–629PubMedGoogle Scholar
  32. Bhatt DL (2008) What makes platelets angry: diabetes, fibrinogen, obesity, and impaired response to antiplatelet therapy? J Am Coll Cardiol 52:1060–1061PubMedGoogle Scholar
  33. Bhatt DL (2009) Tailoring antiplatelet therapy based on pharmacogenomics: how well do the data fit? JAMA 302:896–897PubMedGoogle Scholar
  34. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD et al (2008) ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 118:1894–1909PubMedGoogle Scholar
  35. Bhindi R, Ormerod O, Newton J, Banning AP, Testa L (2008) Interaction between statins and clopidogrel: is there anything clinically relevant? QJM 101:915–925PubMedGoogle Scholar
  36. Bliden KP, DiChiara J, Lawal L, Singla A, Antonino MJ, Baker BA et al (2008) The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 52:531–533PubMedGoogle Scholar
  37. Bobbert P, Stellbaum C, Steffens D, Schutte C, Bobbert T, Schultheiss HP et al (2012) Postmenopausal women have an increased maximal platelet reactivity compared to men despite dual antiplatelet therapy. Blood Coagul Fibrinolysis 23:723–728PubMedGoogle Scholar
  38. Bonello L, Camoin-Jau L, Mancini J, Bessereau J, Grosdidier C, Alessi MC et al (2012) Factors associated with the failure of clopidogrel dose-adjustment according to platelet reactivity monitoring to optimize P2Y12-ADP receptor blockade. Thromb Res 130:70–74PubMedGoogle Scholar
  39. Bonello-Palot N, Armero S, Paganelli F, Mancini J, De Labriolle A, Bonello C et al (2009) Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention. Am J Cardiol 104:1511–1515PubMedGoogle Scholar
  40. Bordeaux BC, Qayyum R, Yanek LR, Vaidya D, Becker LC, Faraday N et al (2010) Effect of obesity on platelet reactivity and response to low-dose aspirin. Prev Cardiol 13:56–62PubMedGoogle Scholar
  41. Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C et al (2011) Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 17:110–116PubMedGoogle Scholar
  42. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS et al (2007a) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5:2429–2436PubMedGoogle Scholar
  43. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS et al (2007b) A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153:66–76PubMedGoogle Scholar
  44. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R et al (2007) Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 49:2312–2317PubMedGoogle Scholar
  45. Caplain H, Donat F, Gaud C, Necciari J (1999) Pharmacokinetics of clopidogrel. Semin Thromb Hemost 25(Suppl 2):25–28PubMedGoogle Scholar
  46. Capodanno D, Bhatt DL, Goto S, O’Donoghue ML, Moliterno DJ, Tamburino C et al (2012) Safety and efficacy of protease-activated receptor-1 antagonists in patients with coronary artery disease: a meta-analysis of randomized clinical trials. J Thromb Haemost 10:2006–2015PubMedGoogle Scholar
  47. Cattaneo M, Zighetti ML, Lombardi R, Martinez C, Lecchi A, Conley PB et al (2003) Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci U S A 100:1978–1983PubMedCentralPubMedGoogle Scholar
  48. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R et al (2005) Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366:1607–1621PubMedGoogle Scholar
  49. Chen M, Ma L, Drusano GL, Bertino JS Jr, Nafziger AN (2006) Sex differences in CYP3A activity using intravenous and oral midazolam. Clin Pharmacol Ther 80:531–538PubMedGoogle Scholar
  50. Chen BL, Chen Y, Tu JH, Li YL, Zhang W, Li Q et al (2009) Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole related to CYP2C19 genetic polymorphisms. J Clin Pharmacol 49:574–581PubMedGoogle Scholar
  51. Chen CY, Poole EM, Ulrich CM, Kulmacz RJ, Wang LH (2012) Functional analysis of human thromboxane synthase polymorphic variants. Pharmacogenet Genomics 22:653–658PubMedGoogle Scholar
  52. Clarke TA, Waskell LA (2003) The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos 31:53–59PubMedGoogle Scholar
  53. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J et al (2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373:309–317PubMedGoogle Scholar
  54. Collet JP, Cuisset T, Range G, Cayla G, Elhadad S, Pouillot C et al (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:2100–2109PubMedGoogle Scholar
  55. Collins SD, Torguson R, Gaglia MA Jr, Lemesle G, Syed AI, Ben Dor I et al (2010) Does black ethnicity influence the development of stent thrombosis in the drug-eluting stent era? Circulation 122:1085–1090PubMedGoogle Scholar
  56. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S et al (2009) Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 360:2066–2078PubMedGoogle Scholar
  57. Cuisset T, Frere C, Quilici J, Barbou F, Morange PE, Hovasse T et al (2006) High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 4:542–549PubMedGoogle Scholar
  58. Cuisset T, Frere C, Quilici J, Morange PE, Saut N, Lambert M et al (2007) 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. Thromb Res 120:893–899PubMedGoogle Scholar
  59. d’Esposito F, Nebot N, Edwards RJ, Murray M (2010) Impaired irinotecan biotransformation in hepatic microsomal fractions from patients with chronic liver disease. Br J Clin Pharmacol 70:400–408PubMedCentralPubMedGoogle Scholar
  60. Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494PubMedGoogle Scholar
  61. Davi G, Guagnano MT, Ciabattoni G, Basili S, Falco A, Marinopiccoli M et al (2002) Platelet activation in obese women: role of inflammation and oxidant stress. JAMA 288:2008–2014PubMedGoogle Scholar
  62. Debrunner M, Schuiki E, Minder E, Straumann E, Naegeli B, Mury R et al (2008) Proinflammatory cytokines in acute myocardial infarction with and without cardiogenic shock. Clin Res Cardiol 97:298–305PubMedGoogle Scholar
  63. Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP (2003) Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101:3908–3914PubMedGoogle Scholar
  64. Ding XL, Xie C, Miao LY (2012) Effects of CYP2C19 *2 and *3 as well as CES1A2 -816A/C genetic polymorphisms on clopidogrel-mediated platelet aggregation. In: The 13rd national meeting of Chinese Society for Clinical Pharmacology, Chengdu, October 26–28, pp 186 (abstract)Google Scholar
  65. Dinicolantonio JJ, Serebruany VL (2012) Angiotensin receptor blockers worsen renal function and dyspnea on ticagrelor: a potential ticagrelor-angiotensin receptor blocker interaction? Clin Cardiol 36:647–648Google Scholar
  66. Dorsam RT, Kunapuli SP (2004) Central role of the P2Y12 receptor in platelet activation. J Clin Invest 113:340–345PubMedCentralPubMedGoogle Scholar
  67. Erlinge D, Varenhorst C, Braun OO, James S, Winters KJ, Jakubowski JA et al (2008) Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 52:1968–1977PubMedGoogle Scholar
  68. Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS, Brandt JT et al (2007) Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 81:735–741PubMedGoogle Scholar
  69. Fatini C, Sticchi E, Bolli P, Marcucci R, Giusti B, Paniccia R et al (2009) eNOS gene influences platelet phenotype in acute coronary syndrome patients on dual antiplatelet treatment. Platelets 20:548–554PubMedGoogle Scholar
  70. Feher G, Koltai K, Alkonyi B, Papp E, Keszthelyi Z, Kesmarky G et al (2007) Clopidogrel resistance: role of body mass and concomitant medications. Int J Cardiol 120:188–192PubMedGoogle Scholar
  71. Feit F, Voeltz MD, Attubato MJ, Lincoff AM, Chew DP, Bittl JA et al (2007) Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol 100:1364–1369PubMedGoogle Scholar
  72. Feliste R, Delebassee D, Simon MF, Chap H, Defreyn G, Vallee E et al (1987) Broad spectrum anti-platelet activity of ticlopidine and PCR 4099 involves the suppression of the effects of released ADP. Thromb Res 48:403–415PubMedGoogle Scholar
  73. Fichtlscherer S, Dimmeler S, Breuer S, Busse R, Zeiher AM, Fleming I (2004) Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. Circulation 109:178–183PubMedGoogle Scholar
  74. Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL et al (2010) Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 116:280–286PubMedCentralPubMedGoogle Scholar
  75. Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M et al (2003) Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 108:989–995PubMedGoogle Scholar
  76. Fontana P, Hulot JS, De Moerloose P, Gaussem P (2007) Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 5:2153–2155PubMedGoogle Scholar
  77. Fontana P, Berdague P, Castelli C, Nolli S, Barazer I, Fabbro-Peray P et al (2010) Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study. J Thromb Haemost 8:2614–2623PubMedGoogle Scholar
  78. Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N et al (2008) Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 101:1088–1093PubMedGoogle Scholar
  79. Friedman DJ, Talbert ME, Bowden DW, Freedman BI, Mukanya Y, Enjyoji K et al (2009) Functional ENTPD1 polymorphisms in African Americans with diabetes and end-stage renal disease. Diabetes 58:999–1006PubMedCentralPubMedGoogle Scholar
  80. Ganesan S, Williams C, Maslen CL, Cherala G (2013) Clopidogrel variability: role of plasma protein binding alterations. Br J Clin Pharmacol 75:1468–1477Google Scholar
  81. Geiger J, Brich J, Honig-Liedl P, Eigenthaler M, Schanzenbacher P, Herbert JM et al (1999) Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 19:2007–2011PubMedGoogle Scholar
  82. Geisler T, Langer H, Wydymus M, Gohring K, Zurn C, Bigalke B et al (2006) Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 27:2420–2425PubMedGoogle Scholar
  83. Geisler T, Grass D, Bigalke B, Stellos K, Drosch T, Dietz K et al (2008a) The residual platelet aggregation after deployment of intracoronary stent (PREDICT) score. J Thromb Haemost 6:54–61PubMedGoogle Scholar
  84. Geisler T, Schaeffeler E, Dippon J, Winter S, Buse V, Bischofs C et al (2008b) CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 9:1251–1259PubMedGoogle Scholar
  85. George J, Murray M, Byth K, Farrell GC (1995) Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 21:120–128PubMedGoogle Scholar
  86. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J (2006) Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost 4:2508–2509PubMedGoogle Scholar
  87. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R et al (2007) Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 17:1057–1064PubMedGoogle Scholar
  88. Giusti B, Gori AM, Marcucci R, Sestini I, Saracini C, Paniccia R et al (2008) Role of glycoprotein Ia gene polymorphisms in determining platelet function in myocardial infarction patients undergoing percutaneous coronary intervention on dual antiplatelet treatment. Atherosclerosis 196:341–348PubMedGoogle Scholar
  89. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R et al (2009) Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 103:806–811PubMedGoogle Scholar
  90. Gong IY, Crown N, Suen CM, Schwarz UI, Dresser GK, Knauer MJ et al (2012) Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response. Eur Heart J 33:2856–2864PubMedGoogle Scholar
  91. Gonzales RJ, Ghaffari AA, Duckles SP, Krause DN (2005) Testosterone treatment increases thromboxane function in rat cerebral arteries. Am J Physiol Heart Circ Physiol 289:H578–H585PubMedGoogle Scholar
  92. Gurbel PA, Anderson RD (1997) New concept in coronary angioplasty: dilatation with a helical balloon that allows simultaneous autoperfusion. Cathet Cardiovasc Diagn 40:109–116PubMedGoogle Scholar
  93. Gurbel PA, Tantry US (2006) Drug insight: clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 3:387–395PubMedGoogle Scholar
  94. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107:2908–2913PubMedGoogle Scholar
  95. Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP et al (2005a) Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 46:1820–1826PubMedGoogle Scholar
  96. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US (2005b) The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 45:1392–1396PubMedGoogle Scholar
  97. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ et al (2005c) Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 46:1827–1832PubMedGoogle Scholar
  98. Gurbel PA, Lau WC, Tantry US (2008) Omeprazole: a possible new candidate influencing the antiplatelet effect of clopidogrel. J Am Coll Cardiol 51:261–263PubMedGoogle Scholar
  99. Guzauskas GF, Hughes DA, Bradley SM, Veenstra DL (2012) A risk-benefit assessment of prasugrel, clopidogrel, and genotype-guided therapy in patients undergoing percutaneous coronary intervention. Clin Pharmacol Ther 91:829–837PubMedGoogle Scholar
  100. Hagihara K, Nishiya Y, Kurihara A, Kazui M, Farid NA, Ikeda T (2008) Comparison of human cytochrome P450 inhibition by the thienopyridines prasugrel, clopidogrel, and ticlopidine. Drug Metab Pharmacokinet 23:412–420PubMedGoogle Scholar
  101. Hanley MJ, Abernethy DR, Greenblatt DJ (2010) Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 49:71–87PubMedGoogle Scholar
  102. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695PubMedGoogle Scholar
  103. Harmsze AM, van Werkum JW, ten Berg JM, Hackeng CM, Deneer VH (2009) Concomitant use of sulfonylurea antidiabetics attenuates on-clopidogrel platelet reactivity. Circulation 120:S501 (abstract)Google Scholar
  104. Harmsze A, van Werkum JW, Bouman HJ, Ruven HJ, Breet NJ, ten Berg JM et al (2010) Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics 20:18–25PubMedGoogle Scholar
  105. Hasan MS, Basri HB, Hin LP, Stanslas J (2013) Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Int J Neurosci 123:143–154PubMedGoogle Scholar
  106. Hechler B, Zhang Y, Eckly A, Cazenave JP, Gachet C, Ravid K (2003) Lineage-specific overexpression of the P2Y1 receptor induces platelet hyper-reactivity in transgenic mice. J Thromb Haemost 1:155–163PubMedGoogle Scholar
  107. Helton TJ, Bavry AA, Kumbhani DJ, Duggal S, Roukoz H, Bhatt DL (2007) Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials. Am J Cardiovasc Drugs 7:289–297PubMedGoogle Scholar
  108. Herbert JM, Savi P (2003) P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med 3:113–122PubMedGoogle Scholar
  109. Hermosillo AJ, Spinler SA (2008) Aspirin, clopidogrel, and warfarin: is the combination appropriate and effective or inappropriate and too dangerous? Ann Pharmacother 42:790–805PubMedGoogle Scholar
  110. Hetherington SL, Singh RK, Lodwick D, Thompson JR, Goodall AH, Samani NJ (2005) Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol 25:252–257PubMedGoogle Scholar
  111. Hirschowitz BI, Hawkey CJ (2001) Questions regarding future research on aspirin and the gastrointestinal tract. Am J Med 110:74S–78SPubMedGoogle Scholar
  112. Hirsh J, Dalen JE, Fuster V, Harker LB, Patrono C, Roth G (1995) Aspirin and other platelet-active drugs. The relationship among dose, effectiveness, and side effects. Chest 108:247S–257SPubMedGoogle Scholar
  113. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED et al (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 301:937–944PubMedGoogle Scholar
  114. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M et al (2006) Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 48:1742–1750PubMedGoogle Scholar
  115. Hochholzer W, Trenk D, Fromm MF, Valina CM, Stratz C, Bestehorn HP et al (2010) Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 55:2427–2434PubMedGoogle Scholar
  116. Holinstat M, Voss B, Bilodeau ML, McLaughlin JN, Cleator J, Hamm HE (2006) PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. J Biol Chem 281:26665–26674PubMedCentralPubMedGoogle Scholar
  117. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207PubMedGoogle Scholar
  118. Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM (2010) 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. Circulation 122:537–557PubMedGoogle Scholar
  119. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C et al (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247PubMedGoogle Scholar
  120. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O et al (2010) Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 56:134–143PubMedGoogle Scholar
  121. Humbert M, Nurden P, Bihour C, Pasquet JM, Winckler J, Heilmann E et al (1996) Ultrastructural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation. Arterioscler Thromb Vasc Biol 16:1532–1543PubMedGoogle Scholar
  122. Hurbin F, Boulenc X, Daskalakis N, Farenc C, Taylor T, Bonneau D et al (2012) Clopidogrel pharmacodynamics and pharmacokinetics in the fed and fasted state: a randomized crossover study of healthy men. J Clin Pharmacol 52:1506–1515PubMedGoogle Scholar
  123. Iijima R, Ndrepepa G, Mehilli J, Byrne RA, Schulz S, Neumann FJ et al (2009) Profile of bleeding and ischaemic complications with bivalirudin and unfractionated heparin after percutaneous coronary intervention. Eur Heart J 30:290–296PubMedGoogle Scholar
  124. Ishida F, Furihata K, Ishida K, Yan J, Kitano K, Kiyosawa K et al (1995) The largest variant of platelet glycoprotein Ib alpha has four tandem repeats of 13 amino acids in the macroglycopeptide region and a genetic linkage with methionine145. Blood 86:1357–1360PubMedGoogle Scholar
  125. Jacobson AK (2004) Platelet ADP receptor antagonists: ticlopidine and clopidogrel. Best Pract Res Clin Haematol 17:55–64PubMedGoogle Scholar
  126. Jang JS, Cho KI, Jin HY, Seo JS, Yang TH, Kim DK et al (2012) Meta-analysis of cytochrome P450 2C19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel. Am J Cardiol 110:502–508PubMedGoogle Scholar
  127. Jernas M, Olsson B, Arner P, Jacobson P, Sjostrom L, Walley A et al (2009) Regulation of carboxylesterase 1 (CES1) in human adipose tissue. Biochem Biophys Res Commun 383:63–67PubMedCentralPubMedGoogle Scholar
  128. Jin RC, Voetsch B, Loscalzo J (2005) Endogenous mechanisms of inhibition of platelet function. Microcirculation 12:247–258PubMedGoogle Scholar
  129. Jinnai T, Horiuchi H, Makiyama T, Tazaki J, Tada T, Akao M et al (2009) Impact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in Japan. Circ J 73:1498–1503PubMedGoogle Scholar
  130. Johnson JA, Roden DM, Lesko LJ, Ashley E, Klein TE, Shuldiner AR (2012) Clopidogrel: a case for indication-specific pharmacogenetics. Clin Pharmacol Ther 91:774–776PubMedCentralPubMedGoogle Scholar
  131. Jones CI, Bray S, Garner SF, Stephens J, de Bono B, Angenent WG et al (2009) A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways. Blood 114:1405–1416PubMedGoogle Scholar
  132. Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S et al (1998) A dual thrombin receptor system for platelet activation. Nature 394:690–694PubMedGoogle Scholar
  133. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O et al (2010) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38:92–99PubMedGoogle Scholar
  134. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199PubMedGoogle Scholar
  135. Kim KA, Park PW, Hong SJ, Park JY (2008a) The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 84:236–242PubMedGoogle Scholar
  136. Kim KA, Park PW, Park JY (2008b) Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects. Eur J Clin Pharmacol 64:589–597PubMedGoogle Scholar
  137. Kimura M, Ieiri I, Wada Y, Mamiya K, Urae A, Iimori E et al (1999) Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy. Br J Clin Pharmacol 47:115–119PubMedCentralPubMedGoogle Scholar
  138. King SB III, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK, Morrison DA, Williams DO et al (2008) 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 117:261–295PubMedGoogle Scholar
  139. Kinnaird TD, Stabile E, Mintz GS, Lee CW, Canos DA, Gevorkian N et al (2003) Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 92:930–935PubMedGoogle Scholar
  140. Kotlyar M, Carson SW (1999) Effects of obesity on the cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 37:8–19PubMedGoogle Scholar
  141. Kuijpers RW, Faber NM, Cuypers HT, Ouwehand WH, dem Borne AE (1992) NH2-terminal globular domain of human platelet glycoprotein Ib alpha has a methionine 145/threonine145 amino acid polymorphism, which is associated with the HPA-2 (Ko) alloantigens. J Clin Invest 89:381–384PubMedCentralPubMedGoogle Scholar
  142. Kulkarni S, Dopheide SM, Yap CL, Ravanat C, Freund M, Mangin P et al (2000) A revised model of platelet aggregation. J Clin Invest 105:783–791PubMedCentralPubMedGoogle Scholar
  143. Kunicki TJ, Kritzik M, Annis DS, Nugent DJ (1997) Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood 89:1939–1943PubMedGoogle Scholar
  144. Latry P, Martin-Latry K, Lafitte M, Peter C, Couffinhal T (2012) Dual antiplatelet therapy after myocardial infarction and percutaneous coronary intervention: analysis of patient adherence using a French health insurance reimbursement database. EuroIntervention 7:1413–1419PubMedGoogle Scholar
  145. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS et al (2003) Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 107:32–37PubMedGoogle Scholar
  146. Lau WC, Welch TD, Shields T, Rubenfire M, Tantry US, Gurbel PA (2011) The effect of St. John’s Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: Increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol 57:86–93PubMedGoogle Scholar
  147. Lee JM, Park S, Shin DJ, Choi D, Shim CY, Ko YG et al (2009) Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am J Cardiol 104:46–51PubMedGoogle Scholar
  148. Lee SJ, Kwon JA, Cho SA, Jarrar YB, Shin JG (2012) Effects of testosterone and 17beta-oestradiol on expression of the G protein-coupled receptor P2Y12 in megakaryocytic DAMI cells. Platelets 23:579–585PubMedGoogle Scholar
  149. Lei HP, Yu XY, Xie HT, Li HH, Fan L, Dai LL et al (2010) Effect of St. John’s wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers. Xenobiotica 40:275–281PubMedGoogle Scholar
  150. Lenain N, Freund M, Leon C, Cazenave JP, Gachet C (2003) Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist. J Thromb Haemost 1:1144–1149PubMedGoogle Scholar
  151. Lev EI, Patel RT, Guthikonda S, Lopez D, Bray PF, Kleiman NS (2007) Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel. Thromb Res 119:355–360PubMedGoogle Scholar
  152. Lewis JP, Horenstein RB, Ryan K, O'Connell JR, Gibson Q, Mitchell BD et al (2013) The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet Genomics 23:1–8PubMedCentralPubMedGoogle Scholar
  153. Li XL, Cao J, Fan L, Ye L, Wang Q, Cui CP et al (2012a) Correlation analysis of aspirin resistance and cyclooxygenase-1 haplotype in old Chinese patients with cardio-cerebrovascular diseases. Chin J Ying Yang Physiol 28:225–229 (in Chinese)Google Scholar
  154. Li Y, Tang HL, Hu YF, Xie HG (2012b) The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients. J Thromb Haemost 10:199–206PubMedGoogle Scholar
  155. Lin SY, Cui HB, Chen XM, Wang SH, Zhou HL, Du WP et al (2012) Clinical application of VerifyNow-P2Y12 assay in evaluation of platelet inhibition efficacy of clopidogrel. Chin J Cardiovasc Dis 40:662–666 (in Chinese)Google Scholar
  156. Lins R, Broekhuysen J, Necciari J, Deroubaix X (1999) Pharmacokinetic profile of 14C-labeled clopidogrel. Semin Thromb Hemost 25(Suppl 2):29–33PubMedGoogle Scholar
  157. Liu YT, Hao HP, Liu CX, Wang GJ, Xie HG (2007) Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab Rev 39:699–721PubMedGoogle Scholar
  158. Liu XL, Wang ZJ, Yang Q, Ge HL, Gao F, Liu YY et al (2010) Impact of CYP2C19 polymorphism and smoking on response to clopidogrel in patients with stable coronary artery disease. Chin Med J 123:3178–3183PubMedGoogle Scholar
  159. Longo DL (2012) Tumor heterogeneity and personalized medicine. N Engl J Med 366:956–957PubMedGoogle Scholar
  160. Lopez JA, Ludwig EH, McCarthy BJ (1992) Polymorphism of human glycoprotein Ib alpha results from a variable number of tandem repeats of a 13-amino acid sequence in the mucin-like macroglycopeptide region. Structure/function implications. J Biol Chem 267:10055–10061PubMedGoogle Scholar
  161. Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA et al (1997) Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 99:2545–2553PubMedCentralPubMedGoogle Scholar
  162. Luchessi AD, Silbiger VN, Cerda A, Hirata RD, Carracedo A, Brion M et al (2012) Increased clopidogrel response is associated with ABCC3 expression: a pilot study. Clin Chim Acta 413:417–421PubMedGoogle Scholar
  163. Malek LA, Kisiel B, Spiewak M, Grabowski M, Filipiak KJ, Kostrzewa G et al (2008) Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J 72:1165–1169PubMedGoogle Scholar
  164. Mani H, Toennes SW, Linnemann B, Urbanek DA, Schwonberg J, Kauert GF et al (2008) Determination of clopidogrel main metabolite in plasma: a useful tool for monitoring therapy? Ther Drug Monit 30:84–89PubMedGoogle Scholar
  165. Mao Z, Li Y, Peng Y, Luan X, Gui H, Feng X et al (2011) Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK-NF-kappaB pathway. Toxicol Lett 201:213–220PubMedGoogle Scholar
  166. Marcus AJ, Safier LB, Hajjar KA, Ullman HL, Islam N, Broekman MJ et al (1991) Inhibition of platelet function by an aspirin-insensitive endothelial cell ADPase. Thromboregulation by endothelial cells. J Clin Invest 88:1690–1696PubMedCentralPubMedGoogle Scholar
  167. Marcus AJ, Broekman MJ, Drosopoulos JH, Islam N, Alyonycheva TN, Safier LB et al (1997) The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39. J Clin Invest 99:1351–1360PubMedCentralPubMedGoogle Scholar
  168. Marcus AJ, Broekman MJ, Drosopoulos JH, Islam N, Pinsky DJ, Sesti C et al (2003) Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases. J Pharmacol Exp Ther 305:9–16PubMedGoogle Scholar
  169. Maree AO, Curtin RJ, Dooley M, Conroy RM, Crean P, Cox D et al (2005) Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease. J Am Coll Cardiol 46:1258–1263PubMedGoogle Scholar
  170. Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33PubMedGoogle Scholar
  171. Maseneni S, Donzelli M, Taegtmeyer AB, Brecht K, Krahenbuhl S (2012) Toxicology of clopidogrel and ticlopidine on human myeloid progenitor cells; Importance of metabolites. Toxicology 299:139–145PubMedGoogle Scholar
  172. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I et al (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109:3171–3175PubMedGoogle Scholar
  173. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al (2009a) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362PubMedGoogle Scholar
  174. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al (2009b) Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 119:2553–2560PubMedGoogle Scholar
  175. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T et al (2010) 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 376:1312–1319PubMedCentralPubMedGoogle Scholar
  176. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK et al (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358:527–533PubMedGoogle Scholar
  177. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB et al (2010) Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 376:1233–1243PubMedGoogle Scholar
  178. Michelson AD, Linden MD, Furman MI, Li Y, Barnard MR, Fox ML et al (2007) Evidence that pre-existent variability in platelet response to ADP accounts for ‘clopidogrel resistance’. J Thromb Haemost 5:75–81PubMedGoogle Scholar
  179. Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC (2004) Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol 93:456–458PubMedGoogle Scholar
  180. Mockel M, Muller R, Vollert JO, Muller C, Danne O, Gareis R et al (2007) Lipoprotein-associated phospholipase A2 for early risk stratification in patients with suspected acute coronary syndrome: a multi-marker approach: the North Wuerttemberg and Berlin Infarction Study-II (NOBIS-II). Clin Res Cardiol 96:604–612PubMedGoogle Scholar
  181. Monton M, Jimenez A, Nunez A, Lopez-Blaya A, Farre J, Gomez J et al (2000) Comparative effects of angiotensin II AT-1-type receptor antagonists in vivo on human platelet activation. J Cardiovasc Pharmacol 35:906–913PubMedGoogle Scholar
  182. Mullangi R, Srinivas NR (2009) Clopidogrel: review of bioanalytical methods, pharmacokinetics/pharmacodynamics, and update on recent trends in drug-drug interaction studies. Biomed Chromatogr 23:26–41PubMedGoogle Scholar
  183. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M (2003) Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 89:783–787PubMedGoogle Scholar
  184. Muller K, Aichele S, Herkommer M, Bigalke B, Stellos K, Htun P et al (2010) Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. Atherosclerosis 213:256–262PubMedGoogle Scholar
  185. Muller C, Caillard S, Jesel L, El Ghannudi S, Ohlmann P, Sauleau E et al (2012) Association of estimated GFR with platelet inhibition in patients treated with clopidogrel. Am J Kidney Dis 59:777–785PubMedGoogle Scholar
  186. Nguyen TA, Diodati JG, Pharand C (2005) Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 45:1157–1164PubMedGoogle Scholar
  187. Nishiya Y, Hagihara K, Ito T, Tajima M, Miura S, Kurihara A et al (2009) Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel. Drug Metab Dispos 37:589–593PubMedGoogle Scholar
  188. Niu H, Chen X, Gruppo RA, Li D, Wang Y, Zhang L et al (2012) Integrin αIIb-mediated PI3k/Akt activation in platelets. PLoS One 7:e47356PubMedCentralPubMedGoogle Scholar
  189. O’Donnell CJ, Larson MG, Feng D, Sutherland PA, Lindpaintner K, Myers RH et al (2001) Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation 103:3051–3056PubMedGoogle Scholar
  190. O’Donoghue M, Wiviott SD (2006) Clopidogrel response variability and future therapies: clopidogrel: does one size fit all? Circulation 114:e600–e606PubMedGoogle Scholar
  191. Ohmori T, Yano Y, Sakata A, Ikemoto T, Shimpo M, Madoiwa S et al (2012) Lack of association between serum paraoxonase-1 activity and residual platelet aggregation during dual anti-platelet therapy. Thromb Res 129:e36–e40PubMedGoogle Scholar
  192. Ostadal P, Ostadal B (2012) Women and the management of acute coronary syndrome. Can J Physiol Pharmacol 90:1151–1159PubMedGoogle Scholar
  193. Ozdemir V, Graham JE, Godard B (2008) Race as a variable in pharmacogenomics science: from empirical ethics to publication standards. Pharmacogenet Genomics 18:837–841PubMedGoogle Scholar
  194. Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J et al (2010) Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 363:1704–1714PubMedGoogle Scholar
  195. Park KW, Park JJ, Lee SP, Oh IY, Suh JW, Yang HM et al (2011) Cilostazol attenuates on-treatment platelet reactivity in patients with CYP2C19 loss of function alleles receiving dual antiplatelet therapy: a genetic substudy of the CILON-T randomised controlled trial. Heart 97:641–647PubMedGoogle Scholar
  196. Park KW, Kang SH, Kang J, Jeon KH, Park JJ, Han JK et al (2012) Enhanced clopidogrel response in smokers is reversed after discontinuation as assessed by VerifyNow assay: additional evidence for the concept of ‘smokers’ paradox’. Heart 98:1000–1006PubMedGoogle Scholar
  197. Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R, Charbonnier B et al (2004a) Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology. Eur Heart J 25:166–181PubMedGoogle Scholar
  198. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G (2004b) Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:234S–264SPubMedGoogle Scholar
  199. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383PubMedGoogle Scholar
  200. Peace A, McCall M, Tedesco T, Kenny D, Conroy RM, Foley D et al (2010) The role of weight and enteric coating on aspirin response in cardiovascular patients. J Thromb Haemost 8:2323–2325PubMedGoogle Scholar
  201. Pena A, Collet JP, Hulot JS, Silvain J, Barthelemy O, Beygui F et al (2009) Can we override clopidogrel resistance? Circulation 119:2854–2857PubMedGoogle Scholar
  202. Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P et al (2002) Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 30:1288–1295PubMedGoogle Scholar
  203. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL et al (2003) Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 108:1682–1687PubMedGoogle Scholar
  204. Petersen JL, Dery JP, Fischi MC, Hernandez AF, Hranitzky PM, Rao SV et al (2003) Highlights from the American College of Cardiology Annual Scientific Sessions 2003: March 28 to April 2, 2003. Am Heart J 146:19–26PubMedGoogle Scholar
  205. Piazuelo E, Fuentes J, Garcia-Gonzalez MA, Jimenez P, Lanas A (2008) A case–control study of the association between polymorphisms of the endothelial nitric oxide synthase and glycoprotein IIIa genes and upper gastrointestinal bleeding in users of low-dose aspirin. Clin Ther 30:121–130PubMedGoogle Scholar
  206. Pignatelli P, De Biase L, Lenti L, Tocci G, Brunelli A, Cangemi R et al (2005) Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure. Blood 106:1992–1994PubMedGoogle Scholar
  207. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ et al (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329:15–19PubMedCentralPubMedGoogle Scholar
  208. Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP et al (2008) Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 29:992–1000PubMedGoogle Scholar
  209. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D et al (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305:1097–1105PubMedGoogle Scholar
  210. Pulley JM, Denny JC, Peterson JF, Bernard GR, Vnencak-Jones CL, Ramirez AH et al (2012) Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin Pharmacol Ther 92:87–95PubMedCentralPubMedGoogle Scholar
  211. Quinn MJ, Fitzgerald DJ (1999) Ticlopidine and clopidogrel. Circulation 100:1667–1672PubMedGoogle Scholar
  212. Rahimi R, Abdollahi M (2012) An update on the ability of St.John’s wort to affect the metabolism of other drugs. Expert Opin Drug Metab Toxicol 8:691–708PubMedGoogle Scholar
  213. Ramsjo M, Aklillu E, Bohman L, Ingelman-Sundberg M, Roh HK, Bertilsson L (2010) CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking. Eur J Clin Pharmacol 66:871–877PubMedGoogle Scholar
  214. Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K et al (2010) Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med 152:337–345PubMedCentralPubMedGoogle Scholar
  215. Reist M, Roy-de Vos M, Montseny JP, Mayer JM, Carrupt PA, Berger Y et al (2000) Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation. Drug Metab Dispos 28:1405–1410PubMedGoogle Scholar
  216. Richter T, Murdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M et al (2004) Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 308:189–197PubMedGoogle Scholar
  217. Rivera J, Lozano ML, Navarro-Nunez L, Vicente V (2009) Platelet receptor and signaling in the dynamics of thrombus formation. Haematologica 94:700–711PubMedCentralPubMedGoogle Scholar
  218. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M et al (2012) Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 379:1705–1711PubMedGoogle Scholar
  219. Roden DM, Shuldiner AR (2010) Responding to the Clopidogrel Warning by the US Food and Drug Administration. Real life is complicated. Circulation 122:445–448PubMedCentralPubMedGoogle Scholar
  220. Roden DM, Stein CM (2009) Clopidogrel and the concept of high-risk pharmacokinetics. Circulation 119:2127–2130PubMedGoogle Scholar
  221. Ruiz ML, Rigalli JP, Arias A, Villanueva S, Banchio C, Vore M et al (2013) Induction of hepatic multidrug resistance associated protein 3 by ethynylestradiol in independent of cholestasis and mediated by estrogen receptor. Drug Metab Dispos 41:275–280PubMedGoogle Scholar
  222. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P et al (2005) Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179–1189PubMedGoogle Scholar
  223. Sachdeva A, Bavisetty S, Beckham G, Shen AY, Aharonian V, Mansulonani P et al (2012) Discontinuation of long-term clopidogrel therapy is associated with death and myocardial infarction after saphenous vein graft percutaneous coronary intervention. J Am Coll Cardiol 60:2357–2363PubMedGoogle Scholar
  224. Sadler JE (2010) Redeeming ristocetin. Blood 116:155–156PubMedGoogle Scholar
  225. Sai K, Saito Y, Tatewaki N, Hosokawa M, Kaniwa N, Nishimaki-Mogami T et al (2010) Association of carboxylesterase 1A genotypes with irinotecan pharmacokinetics in Japanese cancer patients. Br J Clin Pharmacol 70:222–233PubMedCentralPubMedGoogle Scholar
  226. Sambu N, Radhakrishnan A, Dent H, Calver AL, Corbett S, Gray H et al (2012) Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry. Heart 98:706–711PubMedGoogle Scholar
  227. Sangkuhl K, Klein TE, Altman RB (2010) Clopidogrel pathway. Pharmacogenet Genomics 20:463–465PubMedCentralPubMedGoogle Scholar
  228. Sato Y, Miyashita A, Iwatsubo T, Usui T (2012a) Conclusive identification of the oxybutynin-hydrolyzing enzyme in human liver. Drug Metab Dispos 40:902–906PubMedGoogle Scholar
  229. Sato Y, Miyashita A, Iwatsubo T, Usui T (2012b) Simultaneous absolute protein quantification of carboxylesterases 1 and 2 in human liver tissue fractions using liquid chromatography-tandem mass spectrometry. Drug Metab Dispos 40:1389–1396PubMedGoogle Scholar
  230. Savi P, Herbert JM (2005) Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 31:174–183PubMedGoogle Scholar
  231. Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J et al (1992) Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol 44:527–532PubMedGoogle Scholar
  232. Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y et al (1994a) The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 72:313–317PubMedGoogle Scholar
  233. Savi P, Laplace MC, Maffrand JP, Herbert JM (1994b) Binding of [3H]-2-methylthio ADP to rat platelets–effect of clopidogrel and ticlopidine. J Pharmacol Exp Ther 269:772–777PubMedGoogle Scholar
  234. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP et al (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 84:891–896PubMedGoogle Scholar
  235. Saw J, Brennan DM, Steinhubl SR, Bhatt DL, Mak KH, Fox K et al (2007) Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J Am Coll Cardiol 50:291–295PubMedGoogle Scholar
  236. Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, Asante-Poku S, Zanger UM et al (2001) Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 358:383–384PubMedGoogle Scholar
  237. Schneider DJ (2011) Anti-platelet therapy: glycoprotein IIb-IIIa antagonists. Br J Clin Pharmacol 72:672–682PubMedCentralPubMedGoogle Scholar
  238. Schrenk D, Brockmeier D, Morike K, Bock KW, Eichelbaum M (1998) A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Eur J Clin Pharmacol 53:361–367PubMedGoogle Scholar
  239. Schroeder WS, Ghobrial L, Gandhi PJ (2006) Possible mechanisms of drug-induced aspirin and clopidogrel resistance. J Thromb Thrombolysis 22:139–150PubMedGoogle Scholar
  240. Schwemmer M, Sommer O, Bassenge E (2001) Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling. Cardiovasc Drugs Ther 15:301–307PubMedGoogle Scholar
  241. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA et al (2011) Clinical pharmacogenomics of implementation consortium guidelines for cytochrome P450-2c19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90:328–332PubMedCentralPubMedGoogle Scholar
  242. Serebruany VL, Oshrine BR, Malinin AI, Atar D, Michelson AD, Ferguson JJ III (2005) Noncompliance in cardiovascular clinical trials. Am Heart J 150:882–886PubMedGoogle Scholar
  243. Shahabi P, Siest G, Visvikis-Siest S (2012) Clinical interest of point-of-care pharmacogenomic testing: clopidogrel behind warfarin. Pharmacogenomics 13:1215–1218PubMedGoogle Scholar
  244. Shankar H, Garcia A, Prabhaker J, Kim S, Kunapuli SP (2006) P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost 4:638–647PubMedGoogle Scholar
  245. Sharis PJ, Cannon CP, Loscalzo J (1998) The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 129:394–405PubMedGoogle Scholar
  246. Shimasaki Y, Yasue H, Yoshimura M, Nakayama M, Kugiyama K, Ogawa H et al (1998) Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 31:1506–1510PubMedGoogle Scholar
  247. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB et al (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302:849–857PubMedCentralPubMedGoogle Scholar
  248. Sibbing D, von Beckerath O, Schomig A, Kastrati A, von Beckerath N (2006) P2Y1 gene A1622G dimorphism is not associated with adenosine diphosphate-induced platelet activation and aggregation after administration of a single high dose of clopidogrel. J Thromb Haemost 4:912–914PubMedGoogle Scholar
  249. Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K et al (2009) Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 30:916–922PubMedGoogle Scholar
  250. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J et al (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121:512–518PubMedGoogle Scholar
  251. Sibbing D, Bernlochner I, Schulz S, Massberg S, Schomig A, Mehilli J et al (2012) The impact of smoking on the antiplatelet action of clopidogrel in non-ST-elevation myocardial infarction patients: results from the ISAR-REACT 4 platelet substudy. J Thromb Haemost 10:2199–2202PubMedGoogle Scholar
  252. Siller-Matula JM, Lang I, Christ G, Jilma B (2008) Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 52:1557–1563PubMedGoogle Scholar
  253. Siller-Matula JM, Delle-Karth G, Christ G, Neunteufl T, Maurer G, Huber K et al (2013) Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin. Int J Cardiol 167:430–435Google Scholar
  254. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N et al (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375PubMedGoogle Scholar
  255. Small DS, Farid NA, Li YG, Ernest CS, Payne CD, Salazar DE et al (2008) Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin 24:2251–2257PubMedGoogle Scholar
  256. Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC et al (2006a) AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 113:2363–2372PubMedGoogle Scholar
  257. Smith SM, Judge HM, Peters G, Armstrong M, Fontana P, Gaussem P et al (2006b) Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets 17:250–258PubMedGoogle Scholar
  258. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV (2007) Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 154:221–231PubMedGoogle Scholar
  259. Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF (2011) Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J 11:199–206PubMedGoogle Scholar
  260. Steering Committee CAPRIE (1996) A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk for ischemic events (CAPRIE). Lancet 348:1329–1339Google Scholar
  261. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C et al (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–2420PubMedGoogle Scholar
  262. Storey RF (2009) Clopidogrel in acute coronary syndrome: to genotype or not? Lancet 373:276–278PubMedGoogle Scholar
  263. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M et al (2007) The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost 5:1545–1551PubMedGoogle Scholar
  264. Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ et al (2006) Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 174:1715–1722PubMedCentralPubMedGoogle Scholar
  265. Sun YJ, Li YZ, Jiang DM, Zhang B, Gao Y, Yu HJ et al (2012) Effects of smoke on clinical prognosis of patients with acute ST-segment elevation myocardial infarction. Natl Med J China 92:1963–1966 (in Chinese)Google Scholar
  266. Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, von Beckerath N et al (2004) Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 92:311–316PubMedGoogle Scholar
  267. Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T et al (2006) Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 80:486–501PubMedGoogle Scholar
  268. Tello-Montoliu A, Ferreiro JL, Kodali MK, Ueno M, Tomasello SD, Rollini F et al (2013) Impact of renal function on clopidogrel-induced antiplatelet effects in coronary artery disease patients without diabetes mellitus. J Thromb Thromb 36:14–17Google Scholar
  269. The CURE Trial Investigators (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndrome without ST-elevation. N Engl J Med 345:494–502Google Scholar
  270. Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graffagnino C et al (2003) Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation 108:399–406PubMedGoogle Scholar
  271. Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM et al (2008) 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 Am Coll Cardiol 51:1925–1934PubMedGoogle Scholar
  272. Turpeinen M, Tolonen A, Uusitalo J, Jalonen J, Pelkonen O, Laine K (2005) Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther 77:553–559PubMedGoogle Scholar
  273. Ueno M, Ferreiro JL, Desai B, Tomasello SD, Tello-Montoliu A, Capodanno D et al (2012) Cigarette smoking is associated with a dose–response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. JACC Cardiovasc Interv 5:293–300PubMedGoogle Scholar
  274. Umemura K, Furuta T, Kondo K (2008) The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost 6:1439–1441PubMedGoogle Scholar
  275. Valgimigli M, Minarelli M (2011) Triple antiplatelet therapy in acute coronary syndromes. Drugs 71:1703–1719PubMedGoogle Scholar
  276. Verschuren JJ, Boden H, Wessels JA, van der Hoeven BL, Trompet S, Heijmans BT et al (2012) Value of platelet pharmacogenetics in common clinical practice of patients with ST-segment elevation myocardial infarction. Int J Cardiol (in press)Google Scholar
  277. Vistoli G, Pedretti A, Mazzolari A, Bolchi C, Testa B (2009) Influence of ionization state on the activation of temocapril by hCES1: a molecular-dynamics study. Chem Biodivers 6:2092–2100PubMedGoogle Scholar
  278. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A (2005a) Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 112:2946–2950Google Scholar
  279. von Beckerath N, von Beckerath O, Koch W, Eichinger M, Schomig A, Kastrati A (2005b) P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose. Blood Coagul Fibrinolysis 16:199–204Google Scholar
  280. Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA et al (2008) Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 29:21–30PubMedGoogle Scholar
  281. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J et al (2010) Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 376:1320–1328PubMedGoogle Scholar
  282. Wang GJ, Yang P, Xie HG (2006a) Gene variants in noncoding regions and their possible consequences. Pharmacogenomics 7:203–209PubMedGoogle Scholar
  283. Wang TH, Bhatt DL, Topol EJ (2006b) Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J 27:647–654PubMedGoogle Scholar
  284. Wenaweser P, Dorffler-Melly J, Imboden K, Windecker S, Togni M, Meier B et al (2005) Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 45:1748–1752PubMedGoogle Scholar
  285. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T et al (2010) Guidelines on myocardial revascularization. Eur Heart J 31:2501–2555PubMedGoogle Scholar
  286. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S et al (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015PubMedGoogle Scholar
  287. Wolbold R, Klein K, Burk O, Nussler AK, Neuhaus P, Eichelbaum M et al (2003) Sex is a major determinant of CYP3A4 expression in human liver. Hepatology 38:978–988PubMedGoogle Scholar
  288. Woo JS, Kim W, Lee SR, Jung KH, Kim WS, Lew JH et al (2011) Platelet reactivity in patients with chronic kidney disease receiving adjunctive cilostazol compared with a high-maintenance dose of clopidogrel: results of the effect of platelet inhibition according to clopidogrel dose in patients with chronic kidney disease (PIANO-2 CKD) randomized study. Am Heart J 162:1018–1025PubMedGoogle Scholar
  289. Wurtz M, Kristensen SD, Hvas AM, Grove EL (2012) Pharmacogenetics of the antiplatelet effect of aspirin. Curr Pharm Des 18:5294–5308PubMedGoogle Scholar
  290. Xiao D, Chen YT, Yang D, Yan B (2012) Age-related inducibility of carboxylesterases by the antiepileptic agent phenobarbital and implications in drug metabolism and lipid accumulation. Biochem Pharmacol 84:232–239PubMedGoogle Scholar
  291. Xie HG (1997) Direct evidence for the higher frequency of CYP2C19 allelic heterozygotes in Chinese subjects than in white subjects. Clin Pharmacol Ther 62:691–692PubMedGoogle Scholar
  292. Xie HG (2000) Genetic variations of S-mephenytoin 4′-hydroxylase (CYP2C19) in the Chinese population. Life Sci 66:L175–L181Google Scholar
  293. Xie HG (2010) Personalized immunosuppressive therapy in pediatric heart transplantation: progress, pitfalls and promise. Pharmacol Ther 126:146–158PubMedGoogle Scholar
  294. Xie HG (2011) Chapter 52. Genetically polymorphic cytochrome P450s and transporters and personalized antimicrobial chemotherapy. In: Persing DH, Tenover FC, Tang YW, Nolte FS, Hayden RT, van Belkum A (eds) Molecular microbiology: diagnostic principles and practice, 2nd edn. ASM Press, Washington, DC, pp 803–832Google Scholar
  295. Xie HG, Frueh FW (2005) Pharmacogenomics steps toward personalized medicine. Personalized Med 2:325–337Google Scholar
  296. Xie HG, Kim RB (2005) St John’s wort-associated drug interactions: short-term inhibition and long-term induction? Clin Pharmacol Ther 78:19–24PubMedGoogle Scholar
  297. Xie HG, Huang SL, Xu ZH, Xiao ZS, He N, Zhou HH (1997) Evidence for the effect of gender on activity of (S)-mephenytoin 4′-hydroxylase (CYP2C19) in a Chinese population. Pharmacogenetics 7:115–119PubMedGoogle Scholar
  298. Xie HG, Kim RB, Stein CM, Wilkinson GR, Wood AJ (1999a) Genetic polymorphism of (S)-mephenytoin 4′-hydroxylation in populations of African descent. Br J Clin Pharmacol 48:402–408PubMedCentralPubMedGoogle Scholar
  299. Xie HG, Stein CM, Kim RB, Wilkinson GR, Flockhart DA, Wood AJ (1999b) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9:539–549PubMedGoogle Scholar
  300. Xie HG, Kim RB, Wood AJ, Stein CM (2001) Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 41:815–850PubMedGoogle Scholar
  301. Xie HG, Prasad HC, Kim RB, Stein CM (2002) CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 54:1257–1270PubMedGoogle Scholar
  302. Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5:243–272PubMedGoogle Scholar
  303. Xie HG, Zou JJ, Hu ZY, Zhang JJ, Ye F, Chen SL (2011) Individual variability in the disposition of and response to clopidogrel: pharmacogenomics and beyond. Pharmacol Ther 129:267–289PubMedGoogle Scholar
  304. Yang J, Shi D, Yang D, Song X, Yan B (2007) Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol 72:686–694PubMedGoogle Scholar
  305. Yang J, He MM, Niu W, Wrighton SA, Li L, Liu Y et al (2012) Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes. Br J Clin Pharmacol 73:268–284PubMedCentralPubMedGoogle Scholar
  306. Yasuda SU, Zhang L, Huang SM (2008) The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther 84:417–423PubMedGoogle Scholar
  307. Yousef AM, Arafat T, Bulatova NR, Al Zumyli R (2008) Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel. J Clin Pharm Ther 33:439–449PubMedGoogle Scholar
  308. Zahno A, Brecht K, Bodmer M, Bur D, Tsakiris DA, Krahenbuhl S (2010) Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro. Br J Pharmacol 161:393–404PubMedCentralPubMedGoogle Scholar
  309. Zhang S, Ye J, Zhang Y, Xu X, Liu J, Zhang SH (2013) P2Y(12) protects platelets from apoptosis via PI3K-depedent bak/bax inactivation. J Thromb Haemost 11:149–160PubMedGoogle Scholar
  310. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL et al (2008) Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet 82:1241–1248PubMedCentralPubMedGoogle Scholar
  311. Zhu HJ, Appel DI, Johnson JA, Chavin KD, Markowitz JS (2009) Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril. Biochem Pharmacol 77:1266–1272PubMedGoogle Scholar
  312. Zou JJ, Xie HG, Chen SL, Tan J, Lin L, Zhao YY et al (2013) Influence of CYP2C19 loss-of-function variants on the antiplatelet effects and cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention. Eur J Clin Pharmacol 69:771–777PubMedGoogle Scholar

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© Springer India 2013

Authors and Affiliations

  1. 1.General Clinical Research Center (H.-G.X.), and Department of Neurology (Y.-D.Z.)Nanjing Medical University Nanjing First HospitalNanjingChina
  2. 2.Department of Pharmacology (H.-G.X.)Nanjing Medical University School of PharmacyNanjingChina

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