The H(2)-receptor antagonist ranitidine interferes with clopidogrel-mediated P2Y(12) inhibition in platelets.
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.
Schäfer
Andreas
A
Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Julius-Maximilians-Universität Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
Flierl
Ulrike
U
Pförtsch
Stephanie
S
Seydelmann
Nora
N
Micka
Jan
J
Bauersachs
Johann
J
D000368:Aged; D001792:Blood Platelets / Q000187:drug effects*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy*; D004347:Drug Interactions; D005260:Female; D006635:Histamine H2 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D011899:Ranitidine / Q000494:pharmacology* / Q000627:therapeutic use; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D006635:Histamine H2 Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D011899:Ranitidine; D000077144:Clopidogrel; D013988:Ticlopidine