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
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
H2RA's interact with the cytochrome P-450 (CYP) enzyme mediated activation of
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
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.
- 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.
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.
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.
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
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.
(Plavix) product package insert. Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership. Bridgewater, NJ. May 2009.
- Mega JL, Close SL, Wiviott SD et al. Cytochrome P450 polymorphisms and response to clopidogrel. N Eng J Med 2009;360:354-62.
JM, Lang I, Christ G et al. Calcium-channel blockers reduce the
antiplatelet effect of clopidogrel. J Am Coll Cardiol
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.
NR, Mega JL, Jiang S et al. Interaction between cigarette smoking and
clinical benefit of clopidogrel. J Am Coll Cardiol 2009;53:1273-8.
D, von Beckerath N, Grimberg G et al. Impact of P-glycoprotein on
clopidogrel absorption. Clin Pharmacol Ther 2006;80:486-501.
M, Arvela P, Pelkonen O et al. Effect of five structurally diverse
H2-receptor antagonists on drug metabolism. Biochem Pharmacol
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.
- Kim RB. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev 2002;34:47-54.
WG, Park CS, Roh HK et al. Oxidation of ranitidine by isozymes of
flavin-containing monooxygenase and cytochrome P450. Jpn J Pharmacol
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.
JD. Clinical aspects of the use of clopidogrel, a new antiplatelet
agent. Semin Thromb Hemost 1999;25 Supple 2:77-82.