Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs.
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.
Institute for Translational Medicine and Therapeutics and.
Xuanwen
X
Li
Institute for Translational Medicine and Therapeutics and.
Susanne
S
Fries
Institute of Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104.
Ruizhi
R
Li
Institute for Translational Medicine and Therapeutics and.
John A
JA
Lawson
Institute for Translational Medicine and Therapeutics and Department of Biostatistics and Epidemiology, Perelman School of Medicine, and.
Kathleen J
KJ
Propert
Institute of Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104.
Scott L
SL
Diamond
Institute for Translational Medicine and Therapeutics and.
Ian A
IA
Blair
Institute for Translational Medicine and Therapeutics and.
Garret A
GA
FitzGerald
Institute for Translational Medicine and Therapeutics and tilo@upenn.edu.
Tilo
T
Grosser
D000107:Acetylation; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D006801:Humans; D044085:Microfluidics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051545:Cyclooxygenase 1; D001241:Aspirin
MS; acetylation; aspirin; cyclooxygenase; nonsteroidal antiinflammatory drugs