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Mechanistic Differences in the Antiplatelet Effects of DT‐678 and Existing P2Y 12 Antagonists
Author(s) -
Henderlong Dawn Shirley,
Deters Mackenzie Rae,
Christian Barbara DaShawn,
Lauver Dale Adam
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.819.9
Subject(s) - ticagrelor , clopidogrel , pharmacology , antiplatelet drug , antithrombotic , prodrug , aspirin , ticlopidine , p2y12 , platelet , platelet activation , chemistry , active metabolite , medicine , thrombus , thienopyridine , antagonist , platelet aggregation inhibitor , bleeding time , receptor , pharmacokinetics , platelet aggregation
Arterial thrombosis, leading to tissue ischemia, is the most common cause of death in the developed world. Dual antiplatelet therapy with low dose aspirin and a P2Y 12 antagonist is widely used to prevent thrombus formation. The P2Y 12 antagonist, clopidogrel, is a prodrug that undergoes a complex metabolism process involving cytochrome P450 enzymes (CYP450) to produce the biologically active metabolite (AM). The AM covalently binds to the P2Y 12 receptor on platelets thereby inhibiting receptor activation by ADP resulting in the inhibition of platelet activation. Approximately 60–70% of Asians and 30% of Caucasians carry a genetic polymorphism in the CYP450 that prevents the production of the AM. Our laboratory has previously reported the development of DT‐678, a novel conjugate of the AM that does not require CYP450s. Instead, the drug is nonenzymatically activated through a glutathione exchange reaction. Previous studies have demonstrated that DT‐678 is equally as effective as clopidogrel and ticagrelor at inhibiting platelet activation, while requiring a lower dose than clopidogrel. Additionally, we have shown that while clopidogrel and ticagrelor induce a 1‐ to 2‐fold increase in bleeding time, DT‐678 does not induce a significant increase in bleeding time. The purpose of the present study was to compare the antithrombotic effects of DT‐678 to clopidogrel and ticagrelor after oral administration. To do this, we used a New Zealand white rabbit model of FeCl 3 ‐induced carotid artery injury. All three antiplatelet drugs showed an equal efficacy in prolonging the time to occlusion after FeCl 3 application compared to vehicle. Further data suggest that DT‐678 differentially affects calcium mobilization in platelets and other cell types compared to clopidogrel and ticagrelor after application of 2MeSADP. Together, these data suggest mechanistic differences in the action of DT‐678 compared to existing P2Y 12 antagonists and may explain differences in the bleeding times observed. Support or Funding Information National Institutes of Health National Heart, Lung and Blood Institute [1R43HL139380‐01] This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .