Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response

European Heart Journal

Volumn 33, Issue 22, 2012, Pages 2856-2864

  Gong, Inna Y ^a   Crown, Natalie ^a   Suen, Colin M ^a   Schwarz, Ute I ^a   Dresser, George K ^a   Knauer, Michael J ^a   Sugiyama, Daisuke ^a   Degorter, Marianne K ^a   Woolsey, Sarah ^a   Tirona, Rommel G ^a   Kim, Richard B ^a  

^a WESTERN UNIVERSITY   (Canada)

Author keywords

Antiplatelet response; Clopidogrel; CYP2C19; Pharmacogenetics; Pharmacokinetics; PON1

Indexed keywords

2 OXOCLOPIDOGREL; ARYLDIALKYLPHOSPHATASE 1; CLOPIDOGREL; CYTOCHROME P450 2C19; CYTOCHROME P450 3A4; DRUG METABOLITE; MIDAZOLAM; THIOL; UNCLASSIFIED DRUG;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; DRUG ACTIVATION; DRUG BLOOD LEVEL; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG RESPONSE; DRUG TRANSFORMATION; ENZYME ACTIVITY; GAIN OF FUNCTION MUTATION; GENETIC POLYMORPHISM; GENOTYPE; HETEROLOGOUS EXPRESSION; HUMAN; HUMAN EXPERIMENT; IN VITRO STUDY; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; NORMAL HUMAN; PREDICTIVE VALUE; PRIORITY JOURNAL; SINGLE DRUG DOSE; TANDEM MASS SPECTROMETRY; THROMBOCYTE AGGREGATION INHIBITION; TIME TO MAXIMUM PLASMA CONCENTRATION; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY;

ADOLESCENT; ADULT; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; ARYLDIALKYLPHOSPHATASE; BIOTRANSFORMATION; CYTOCHROME P-450 CYP3A; ENZYME INHIBITORS; HUMANS; MIDAZOLAM; MIDDLE AGED; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; POLYMORPHISM, GENETIC; TICLOPIDINE; YOUNG ADULT;

EID: 84861323788     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehs042     Document Type: Article

References (33)

1. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-533. (Pubitemid 32772726)
2. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM. Identification and biological activity of the active metabolite of clopi-dogrel. Thromb Haemost 2000;84:891-896.
3. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007;154:221-231. (Pubitemid 47069129)
4. Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N, Faille D, Lambert M, Juhan-Vague I, Bonnet JL, Alessi MC. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008;101:1088-1093.
5. Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, Pascal M, Herbert JM, Maffrand JP, Picard C. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002;30:1288-1295. (Pubitemid 35265838)
6. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. 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 2010;38:92-99.
7. Dansette PM, Libraire J, Bertho G, Mansuy D. Metabolic oxidative cleavage of thioesters: evidence for the formation of sulfenic acid intermediates in the bioac-tivation of the antithrombotic prodrugs ticlopidine and clopidogrel. Chem Res Toxicol 2009;22:369-373.
8. Dansette PM, Thebault S, Bertho G, Mansuy D. Formation and fate of a sulfenic acid intermediate in the metabolic activation of the antithrombotic prodrug pra-sugrel. Chem Res Toxicol 2010;23:1268-1274.
9. Tuffal G, Roy S, Lavisse M, Brasseur D, Schofield J, Delesque Touchard N, Savi P, Bremond N, Rouchon MC, Hurbin F, Sultan E. An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. Thromb Haemost 2011;105:696-705.
10. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362.
11. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-375.
12. Verstuyft C, Simon T, Kim RB. Personalized medicine and antiplatelet therapy: ready for prime time? Eur Heart J 2009;30:1943-1963.
13. Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C, Waldmann C, Schmalz HG, ten Berg JM, Taubert D. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011;17:110-116.
14. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui F, Montalescot G. 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 2010;56:134-143.
15. Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopido-grel treatment. N Engl J Med 2010;363:1704-1714.
16. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Afzal R, Pogue J, Yusuf S. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010;363:930-942.
17. Simon T, Bhatt DL, Bergougnan L, Farenc C, Pearson K, Perrin L, Vicaut E, Lacreta F, Hurbin F, Dubar M. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther 2011;90:287-295.
18. Bonello L, Armero S, Ait Mokhtar O, Mancini J, Aldebert P, Saut N, Bonello N, Barragan P, Arques S, Giacomoni MP, Bonello-Burignat C, Bartholomei MN, Dignat-George F, Camoin-Jau L, Paganelli F. Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism. J Am Coll Cardiol 2010;56:1630-1636.
19. Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011;306:2221-2228.
20. Sibbing D, Koch W, Massberg S, Byrne RA, Mehilli J, Schulz S, Mayer K, Bernlochner I, Schomig A, Kastrati A. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J 2011;32:1605-1613.
21. Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, Scott SA, Montalescot G. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv 2011;4:422-428.
22. Simon T, Steg PG, Becquemont L, Verstuyft C, Kotti S, Schiele F, Ferrari E, Drouet E, Grollier G, Danchin N. Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction. Clin Pharmacol Ther 2011;90:561-567.
23. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849-857.
24. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E, Sabate M, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Pignatti PF, Macaya C. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006;26:1895-1900. (Pubitemid 44305347)
25. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Valente S, Antoniucci D, Abbate R, Gensini GF. 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 2007;17:1057-1064. (Pubitemid 351339490)
26. Lin YS, Lockwood GF, Graham MA, Brian WR, Loi CM, Dobrinska MR, Shen DD, Watkins PB, Wilkinson GR, Kharasch ED, Thummel KE. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics 2001;11:781-791. (Pubitemid 33151513)
27. Dansette PM, Rosi J, Bertho G, Mansuy D. Correspondence. Paraoxonase-1 and clopidogrel efficacy. Nat Med 2011;17:1039-1044.
28. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 2009;30:1744-1752.
29. Bal Dit Sollier C, Berge N, Boval B, Dubar M, Drouet L. Differential sensitivity and kinetics of response of different ex vivo tests monitoring functional variability of platelet response to clopidogrel. Thromb Haemost 2010;104:571-581.
30. Varenhorst C, James S, Erlinge D, Braun OO, Brandt JT, Winters KJ, Jakubowski JA, Olofsson S, Wallentin L, Siegbahn A. Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with pra-sugrel or clopidogrel coadministered with aspirin. Am Heart J 2009;157:562 e1-562 e9.
31. Bidet A, Jais C, Puymirat E, Coste P, Nurden A, Jakubowski J, Nurden P. Verify-Now and VASP phosphorylation assays give similar results for patients receiving clopidogrel, but they do not always correlate with platelet aggregation. Platelets 2010;21:94-100.
32. Gaglia MA, Torguson R, Pakala R, Xue Z, Sardi G, Suddath WO, Kent KM, Satler LF, Pichard AD, Waksman R. Correlation between Light Transmission Aggregometry, VerifyNow P2Y12, and VASP-P platelet reactivity assays following percutaneous coronary intervention. J Interv Cardiol 2011;24:529-534.
33. Brar SS, Ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS, Patti G, Breet NJ, Disciascio G, Cuisset T, Dangas G. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention a collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011;58:1945-1954.