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Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel.

Methods

The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method.

Results

There were no significant differences in the mean plasma concentration–time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs.

Conclusion

Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.

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References

  1. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM (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 118:1894–1909

    Article  PubMed  Google Scholar 

  2. Garcia Rodriguez LA, Lin KJ, Hernandez-Diaz S, Johansson S (2011) Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation 123:1108–1115

    Article  PubMed  CAS  Google Scholar 

  3. van Werkum JW, ten Berg JM, Bredenoord AJ (2009) Proton pump inhibitors and clopidogrel: a difficult dilemma. Am Heart J 157:e43

    Article  PubMed  Google Scholar 

  4. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 301:937–944

    Article  PubMed  CAS  Google Scholar 

  5. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J (2008) Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 51:256–260

    Article  PubMed  CAS  Google Scholar 

  6. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM (2009) A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 180:713–718

    Article  PubMed  Google Scholar 

  7. Kwok CS, Loke YK (2010) Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 31:810–823

    PubMed  CAS  Google Scholar 

  8. van Oijen MG, Siersema PD (2011) Effects of proton pump inhibitors in patients receiving clopidogrel: meta-analysis versus clinical practice. Drug Saf 34:173

    Article  PubMed  Google Scholar 

  9. Delavenne X, Basset T, Zufferey P, Malouk N, Laporte S, Mismetti P (2010) Ultra-performance LC MS/MS method for quantification of clopidogrel active metabolite. J Sep Sci 33:1968–1972

    Article  PubMed  CAS  Google Scholar 

  10. Takahashi M, Pang H, Kawabata K, Farid NA, Kurihara A (2008) Quantitative determination of clopidogrel active metabolite in human plasma by LC-MS/MS. J Pharm Biomed Anal 48:1219–1224

    Article  PubMed  CAS  Google Scholar 

  11. Fernando H, Dart AM, Peter K, Shaw JA (2011) Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy. Thromb Haemost 105:933–944

    Article  PubMed  CAS  Google Scholar 

  12. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304:1821–1830

    Article  PubMed  CAS  Google Scholar 

  13. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P (2006) Cytochrome P450 2 C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247

    Article  PubMed  CAS  Google Scholar 

  14. 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 (2009) Association of cytochrome P450 2 C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302:849–857

    Article  PubMed  CAS  Google Scholar 

  15. Sakai T, Aoyama N, Kita T, Sakaeda T, Nishiguchi K, Nishitora Y, Hohda T, Sirasaka D, Tamura T, Tanigawara Y, Kasuga M, Okumura K (2001) CYP2C19 genotype and pharmacokinetics of three proton pump inhibitors in healthy subjects. Pharm Res 18:721–727

    Article  PubMed  CAS  Google Scholar 

  16. Pezalla E, Day D, Pulliadath I (2008) Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 52:1038–1039

    Article  PubMed  Google Scholar 

  17. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B (2009) Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 157:148

    Article  PubMed  Google Scholar 

  18. Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schomig A, Kastrati A, von Beckerath N (2009) Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 101:714–719

    PubMed  CAS  Google Scholar 

  19. Lou HG, Yuan H, Ruan ZR, Jiang B (2010) Simultaneous determination of paracetamol, pseudoephedrine, dextrophan and chlorpheniramine in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:682–688

    Article  PubMed  CAS  Google Scholar 

  20. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A (2005) 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 112:2946–2950

    Google Scholar 

  21. Tantry US, Kereiakes DJ, Gurbel PA (2011) Clopidogrel and proton pump inhibitors: influence of pharmacological interactions on clinical outcomes and mechanistic explanations. JACC Cardiovasc Interv 4:365–380

    Article  PubMed  Google Scholar 

  22. Tsai YW, Wen YW, Huang WF, Chen PF, Kuo KN, Hsiao FY (2011) Cardiovascular and gastrointestinal events of three antiplatelet therapies: clopidogrel, clopidogrel plus proton-pump inhibitors, and aspirin plus proton-pump inhibitors in patients with previous gastrointestinal bleeding. J Gastroenterol 46:39–45

    Article  PubMed  CAS  Google Scholar 

  23. Gurbel PA, Tantry US (2011) Antiplatelet therapy: clopidogrel-PPI interaction, an ongoing controversy. Nat Rev Cardiol 8:7–8

    Article  PubMed  CAS  Google Scholar 

  24. Lin CF, Shen LJ, Wu FL, Bai CH, Gau CS (2012) Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients of acute coronary syndrome in Taiwan. Br J Clin Pharmacol. doi:10.1111/j.1365-2125.2012.04250.x

  25. Schmidt M, Johansen MB, Robertson DJ, Maeng M, Kaltoft A, Jensen LO, Tilsted HH, Botker HE, Sorensen HT, Baron JA (2012) Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Aliment Pharmacol Ther 35:165–174

    Article  PubMed  CAS  Google Scholar 

  26. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S (2009) Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 120:2322–2329

    Article  PubMed  CAS  Google Scholar 

  27. Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, Salazar DE, Winters KJ (2008) Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 48:475–484

    Article  PubMed  CAS  Google Scholar 

  28. Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M (2010) Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 125:e51–54

    Article  PubMed  Google Scholar 

  29. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ (2007) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5:2429–2436

    Article  PubMed  CAS  Google Scholar 

  30. Kim KA, Park PW, Hong SJ, Park JY (2008) The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 84:236–242

    Article  PubMed  CAS  Google Scholar 

  31. 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 6:1439–1441

    Article  PubMed  CAS  Google Scholar 

  32. Ohbuchi M, Noguchi K, Kawamura A, Usui T (2012) Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4. Xenobiotica 42:633–640

    Google Scholar 

  33. Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M, Lardoux H, Coste P, Lefevre T, Drouet E, Mulak G, Bataille V, Ferrieres J, Verstuyft C, Danchin N (2011) Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2 C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of acute ST-Elevation and Non-ST-elevation myocardial infarction (FAST-MI) registry. Circulation 123:474–482

    Article  PubMed  CAS  Google Scholar 

  34. Li XQ, Andersson TB, Ahlstrom M, Weidolf L (2004) Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 32:821–827

    Article  PubMed  CAS  Google Scholar 

  35. Small DS, Payne CD, Kothare P, Yuen E, Natanegara F, Teng Loh M, Jakubowski JA, Richard Lachno D, Li YG, Winters KJ, Farid NA, Ni L, Salazar DE, Tomlin M, Kelly R (2010) Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese and white volunteers: an open-label trial. Clin Ther 32:365–379

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

No additional funding was received.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310009, China

    Jia Wu, Li-Tao Jia, Li-Ming Shao, Jia-Min Chen, Dan-Dan Zhong, Song Xu & Jian-Ting Cai

  2. Department of Clinical Pharmacology, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, 310009, China

    Jia Wu, Li-Tao Jia, Li-Ming Shao, Jia-Min Chen, Dan-Dan Zhong & Song Xu

  3. Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, 310009, China

    Jian-Ting Cai

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  1. Jia Wu
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Wu, J., Jia, LT., Shao, LM. et al. Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers. Eur J Clin Pharmacol 69, 179–187 (2013). https://doi.org/10.1007/s00228-012-1329-z

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  • DOI: https://doi.org/10.1007/s00228-012-1329-z

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