Abstract 10243: Remarkable Differences in the Effect of Individual Nonsteroidal Anti-Inflammatory Drugs on the Antiplatelet Action of Aspirin
Background and aims: Nonsteroidal anti-inflammtory drugs (NSAIDs) have been reported to prevent platelet inhibition by aspirin. However, it has been suggested that some NSAIDs do not interfere with aspirin. We have studied the molecular interaction of various NSAIDs with cyclooxygenase (COX-1) and whether this is related to the decrease in aspirin's antiplatelet effect in presence of NSAIDs.
Methods: Molecular docking studies (Molegro Virtual Docker, MolDock module) have been performed to examine interactions of NSAIDs with amino acids present in the COX-1 substrate channel (PDB ID: 1PGG). Ibuprofen, naproxen, diclofenac, nimesulide, ketoprofen, oxaprozin, piroxicam, flufenamic acid, dipyrone, ketorolac and celecoxib were examined. The predicted interactions of these compounds with aspirin were verified experimentally using arachidonic acid-induced aggregation and thromboxane formation in platelet rich plasma from healthy donors.
Results: In silico docking showed an interaction of NSAIDs mainly with Ser 530, Arg 120, Tyr 385, Tyr 355 and Trp 387 in the COX-1 substrate channel. Among the NSAIDs studied, ibuprofen, naproxen, nimesulide, oxaprozin, piroxicam, flufenamic acid, dipyrone and celecoxib formed hydrogen bonds with Ser 530, Arg 120 or Tyr 385. These amino acids interact with aspirin prior to acetylation of Ser 530. While aspirin completely (>95%) inhibited platelet aggregation and TX formation in vitro, these NSAIDs partially or completely prevented this inhibition at micromolar concentrations. For example, ibuprofen, naproxen and nimesulide (each 10 µM) restored platelet TX formation in presence of aspirin from less than 4 % (control without aspirin) to 44 ± 6, 14 ± 6 and 55 ± 9 %, respectively (each p<0.05 vs. control). Comparable results were obtained for aggregation. Remarkably, diclofenac, ketorolac and ketoprofen, which did not interfere in docking studies, did not prevent platelet inhibition by aspirin in vitro.
Conclusion: Considerable differences exist between NSAIDs with respect to their interaction with aspirin. Diclofenac, ketorolac and ketoprofen appear not to interfere with aspirin and may be preferable for analgesic treatment in patients receiving antithrombotic therapy with aspirin.
- © 2011 by American Heart Association, Inc.