This topic is related to whether or not there are drug interactions between histamine-2 receptor antagonists (H2RA; cimetidine (Tagamet), famotidine (Pepcid; Fluxid ODT), nizatidine (Axid), and ranitidine (Zantac)) and clopidogrel (Plavix).  This may come up in practice since there is a known interaction between the coadministration of proton pump inhibitors (PPI) and clopidogrel in patients with drug-eluting stents.1-3 

As a reminder, this combination of antiplatelet drug therapy (clopidogrel and aspirin) in patients with drug eluting stents is, unfortunately, known to increase the patient's risk for clinically relevant gastrointestinal (GI) bleeding.4  The potential for this adverse event has become increasingly important since the publication of a position statement sponsored by the American Heart Association (AHA) stating that patients receiving drug eluting stents should receive at least 12 months of aspirin and clopidogrel therapy.5  Due to this change in the standard of care and knowing its potential disadvantages,  the American College of Cardiology Foundation (ACCF), in collaboration with the AHA and American College of Gastroenterology (ACG), published an Expert Consensus Document in 2008 that recommends the addition of a PPI as the preferred class of agents for the treatment and prophylaxis against aspirin-associated GI injury.4  As demonstrated in the previous series, it is now known that some of the PPIs can inhibit the activation of clopidogrel, thereby decreasing its ability to appropriately inhibit platelet aggregation or stent thrombosis.  Therefore, can clinicians replace the PPI with an H2RA without compromising the efficacy of clopidogrel?  Do H2RAs compromise clopidogrel's activation, which is needed in order to result in inhibition of platelets?  

Will H2RA's interact with the cytochrome P-450 (CYP) enzyme mediated activation of clopidogrel?
To review, clopidogrel's metabolism to the activate metabolite appears to undergo sequential activating steps are carried out by CYP1A2, 2B6, 2C9, 2C19, and CYP3A4.6,7  While CYP2C19 has received most of the attention for the activation of clopidogrel, it is known that clopidogrel's activation is multifactorial, as the activity of CYP1A2 and CYP3A4 has also been shown to be influential.1-3,8-10  In addition, while there is conflicting data, it is possible that clopidogrel's absorption in the GI tract can be influence by the efflux cell membrane transporter, P-glycoprotein (P-gp).11  Therefore, if any medication were to influence the activity of any of these pathways, it is possible to affect both the pharmacokinetics and pharmacodynamics of clopidogrel.  Fortunately, most of the H2RAs do not inhibit the CYP enzymes used by clopdigrel.12,13  We are also not aware of any data that H2RAs increase the activity of P-gp.  However, this is not the case for cimetidine which is known to be an inhibitor of CYP1A2 (52% inhibition), CYP2D6 (100% inhibition), and CYP3A4 (64% inhibition).  This is relevant given that changes in CYP1A2 and CYP3A4 activity in other studies has been shown to impact clopidogrel activity.8-10  While there are no known pharmacokinetic studies evaluating the effect of this, cimetidine is also a substrate for P-gp and could theoretically compete with clopidogrel efflux.14  This would however, not impair clopidogrel activity, but would rather increase the bioavailability of clopidogrel since less clopidogrel would be eliminated from the body if cimetidine were competing for its removal.  Lastly, it is important to note that ranitidine is also metabolized by CYP1A2, 2C19, and CYP3A4.15  However, it does not inhibit these enzymes and thus should not interact with clopidogrel activation via CYP enzymes.  A pharmacokinetic drug interaction study showed that ranitidine at 150 mg twice daily did not significantly change the pharmacokinetic profile of clopidogrel given as a 600 mg loading dose followed by 75 mg daily nor did ranitidine affect clopidogrel's ability to inhibit platelet aggregation by light transmission aggregometry.16 

Therefore, it would appear that all of the H2RAs (except cimetidine) are not likely to interact with clopidogrel.  While there are no pharmacokinetic and/or pharmacodynamic drug interactions studies done to date with clopidogrel and cimetidine, one paper suggested that based on the CAPRIE trial, the likelihood of clinically significant drug interactions between clopidogrel and cimetidine would be rare.17  Given the emerging data regarding clinically relevant drug interactions with clopidogrel that in the recent past were not realized, the lack of definitive pharmacokinetic/pharmacodynamic studies between cimetidine and clopidogrel and the ability of cimetidine to inhibit several CYP enzymes, it would be prudent to avoid cimetidine with clopidogrel until further definitive evidence suggests otherwise. 

References:

1. Busti AJ, Herrington JD, Lehew DS et al.  Are there any differences among the proton pump inhibitors (PPIs) in their ability to inhibit the activation of clopidogrel (Plavix®) through the cytochrome P450 (CYP) enzyme system?  PW Drug Interact Newsl 2009;1(24):1-6.
2. Busti AJ, Herrington JD, Lehew DS et al.  What studies are available related to the drug interaction between proton pump inhibitors (PPI) and clopidogrel (Plavix®) on cardiovascular (CV) related endpoints or outcomes?   PW Drug Interact Newsl 2009;1(25):1-5.
   
3. Busti AJ, Herrington JD, Lehew DS et al.  What data are available regarding the efficacy of clopidogrel (Plavix®) on platelet inhibition or reactivity when given with a proton pump inhibitor (PPI)?   PW Drug Interact Newsl 2009;1(26):1-5.
4. Bhatt DL, Scheiman J, Abraham NS et al.  ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risk of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  Circulation  2008;118:1894-909.
5. Grines CL, Bonow RO, Casey DE Jr et al.  Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery disease: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and the American Dental Association, with representation from the American College of Physicians.  Circulation  2007;115:813-8.
   
6. Clopidogrel (Plavix) product package insert.  Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.  Bridgewater, NJ.  May 2009. 
7. Mega JL, Close SL, Wiviott SD et al. Cytochrome P450 polymorphisms and response to clopidogrel.  N Eng J Med 2009;360:354-62. 
   
8. Siller-Matula JM, Lang I, Christ G et al.  Calcium-channel blockers reduce the antiplatelet effect of clopidogrel.  J Am Coll Cardiol  2008;52:1557-63.
9. Farid NA, Payne CD, Small DS et al.  Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently.  Clin Pharmacol Ther  2007;81:735-41.
10. Desai NR, Mega JL, Jiang S et al.  Interaction between cigarette smoking and clinical benefit of clopidogrel.  J Am Coll Cardiol 2009;53:1273-8.
11. Taubert D, von Beckerath N, Grimberg G et al.  Impact of P-glycoprotein on clopidogrel absorption.  Clin Pharmacol Ther  2006;80:486-501.
    
12. Pasanen M, Arvela P, Pelkonen O et al.  Effect of five structurally diverse H2-receptor antagonists on drug metabolism.  Biochem Pharmacol 1986;35:4457-61.
    
13. Martinez C, Albet C, Aqundez JA et al.  Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A4 by H2-receptor antagonists.  Clin Pharmacol Ther  1999;65:369-76.
14. Kim RB.  Drugs as P-glycoprotein substrates, inhibitors, and inducers.  Drug Metab Rev  2002;34:47-54.
    
15. Chung WG, Park CS, Roh HK et al.  Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450.  Jpn J Pharmacol  2000;84:213-220.
16. Small DS, Farid NA, Li YG et al.  Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel.  Curr Med Res Opin  2008;24:2251-7.
    
17. Easton JD.  Clinical aspects of the use of clopidogrel, a new antiplatelet agent.  Semin Thromb Hemost  1999;25 Supple 2:77-82.

Clopidogrel, Plavix, H2RA, Histamine Receptor Antagonist, Famotidine, Pepcid, Ranitidine, Zantac, Axid, Nizatidine, Cimetidine, Tagamet