The H(2)-receptor antagonist ranitidine interferes with clopidogrel-mediated P2Y(12) inhibition in platelets

Pharmacol Res. 2010 Oct;62(4):352-6. doi: 10.1016/j.phrs.2010.05.006. Epub 2010 Jun 4.


Background: Use of proton-pump inhibitors (PPIs) is common in patients on dual antiplatelet therapy (DAT). Recent warnings about potential interactions of PPIs with clopidogrel metabolism leading to impaired DAT efficacy has prompted the recommendation of substituting PPIs with H(2)-receptor antagonists such as ranitidine. We investigated whether ranitidine interacts with P2Y(12) inhibition on the platelet level.

Methods: Blood was collected from 15 patients with stable coronary artery disease, who had undergone elective coronary intervention. Clopidogrel responsiveness was assessed 24h after the administration of a 600mg loading dose using the P2Y(12) specific platelet-reactivity-index (PRI) and light-transmittance aggregometry in the presence and absence of a pharmacologically relevant concentration of the H(2)-receptor antagonist ranitidine (400ng/ml).

Results: Adding ranitidine enhanced P2Y(12)-mediated platelet reactivity to ADP assessed by the PRI (mean PRI+/-SEM: before ranitidine 28+/-5%; after ranitidine 37+/-5%, p=0.0025). Similarly, prostaglandin E1 (PGE(1))-mediated inhibition of ADP-induced aggregation was abrogated in the presence of ranitidine (Agg(max)+/-SEM: before PGE(1) 41+/-2%; after PGE(1) 29+/-2%, p<0.01 vs. before PGE(1); after PGE(1)+ranitidine 42+/-2%, p<0.01 vs. after PGE(1)).

Conclusions: Exposition of platelets with ranitidine significantly enhanced their responsiveness to ADP and contributed to impaired P2Y(12) inhibition suggesting that ranitidine interacts with clopidogrel efficacy through adenylyl cyclase inhibition on the platelet level.

MeSH terms

  • Aged
  • Blood Platelets / drug effects*
  • Clopidogrel
  • Coronary Artery Disease / drug therapy*
  • Drug Interactions
  • Female
  • Histamine H2 Antagonists / pharmacology*
  • Histamine H2 Antagonists / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Platelet Activation / drug effects
  • Purinergic P2Y Receptor Antagonists / pharmacology*
  • Purinergic P2Y Receptor Antagonists / therapeutic use
  • Ranitidine / pharmacology*
  • Ranitidine / therapeutic use
  • Receptors, Purinergic P2Y12 / metabolism*
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology
  • Ticlopidine / therapeutic use


  • Histamine H2 Antagonists
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12
  • Ranitidine
  • Clopidogrel
  • Ticlopidine