Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs
Title | Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Li X, Fries S, Li R, Lawson JA, Propert KJ, Diamond SL, Blair IA, FitzGerald GA, Grosser T |
Journal | Proc Natl Acad Sci U S A |
Volume | 111 |
Issue | 47 |
Pagination | 16830-5 |
Date Published | 2014 Nov 25 |
ISSN | 1091-6490 |
Keywords | Acetylation, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Blood Platelets, Cyclooxygenase 1, Humans, Microfluidics |
Abstract | The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs—ibuprofen, naproxen, and celecoxib—to cause a drug-drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug-drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk. |
DOI | 10.1073/pnas.1406997111 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 25385584 |
PubMed Central ID | PMC4250103 |
Grant List | HL062250 / HL / NHLBI NIH HHS / United States HL103419 / HL / NHLBI NIH HHS / United States HL117798 / HL / NHLBI NIH HHS / United States P30ES013508 / ES / NIEHS NIH HHS / United States U54 HL117798 / HL / NHLBI NIH HHS / United States UL1 TR000003 / TR / NCATS NIH HHS / United States UL1TR000003 / TR / NCATS NIH HHS / United States |