Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin.

Abstract

Previous investigations have shown that ibuprofen inhibits the second wave of platelet aggregation and blocks the conversion of 14 C-arachidonic acid to thromboxane. However, the influence of the drug on platelet function and cyclooxygenase is transitory, lasting only 24 hours. The present study has taken advantage of the shortlived influence of ibuprofen to study its interaction with the long-term effects of aspirin. As expected, both aspirin and ibuprofen supressed platelet cyclooxygenase activity and function, but addition of aspirin to ibuprofen-treated platelets did not increase the degree of inhibition in vitro. Platelet function and prostaglandin synthesis recovered completely 26 hours following ingestion of ibuprofen, but remained compromised 26 hours after taking aspirin. When 650 mg of aspirin was administered after ibuprofen, platelet function and cyclooxygenase activity recovered as completely at 26 hours as did platelets which had been exposed to ibuprofen alone. Thus, prior exposure to ibuprofen in vivo completely protected cyclooxygenase from the irreversible effects of aspirin. Our findings indicate that ibuprofen-like indomethacin and other nonsteroidal antiinf lammatory drugs react with the heme group of cyclooxygenase to prevent arachidonic acid conversion. Since ibuprofen completely blocks the effects of aspirin in platelets in vitro and in vivo, aspirin's primary influence on inhibition of cyclooxygenase must also be through action on the heme portion of the enzyme, rather than acetylation of the protein. 12 Investigations into its mechanism of action several years ago 3 " 5 suggested that it suppressed conversion of arachidonic acid by acetylating the enzyme cyclooxygenase. Other potent inhibitors of prostaglandin formation, however, are incapable of acetylating proteins and must block cyclooxygenase in some other manner.6 " 14 Studies in our laboratory using a cell-free system demonstrated that inhibitors of prostaglandin synthesis (including aspirin, indomethacin, tolmetin, and ibuprofen) prevented arachidonic acid oxidation by interfering with the action of ferrous iron or

Inhibition of Clinical Benefits of Aspirin on First Myocardial Infarction by Nonsteroidal Antiinflammatory Drugs

“…9 Aspirin and NSAIDs share a common docking site on COX-1, providing the possibility of competitive interaction. Basic research findings, 19,20 a crossover study in healthy subjects, 12 and 1 observational study 13 support this hypothesis. In the crossover study by Catella-Lawson et al, 12 concomitant administration of 400 mg ibuprofen every morning antagonized the irreversible platelet inhibition of COX-1 induced by 81 mg aspirin.…”

A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin

“…After 10 min, the reactions were quenched, and the amount of TXB 2 produced was determined by EIA. The data represent the average of (n) titrations from at least three different donors: (A) ibuprofen (10), celecoxib (9), valdecoxib (8), rofecoxib (8), and etoricoxib (6); (B) ibuprofen (11), celecoxib (12), valdecoxib (8), rofecoxib (8), and etoricoxib (6). For celecoxib, only data between 0.005 and 3.7 M are plotted, as higher concentrations showed inhibition from celecoxib alone.…”

“…As the cardioprotective effects of conventional nonselective NSAIDs have not been definitively established, coadministration of low-dose aspirin is recommended for high-risk patients taking NSAIDs for the treatment of inflammatory disorders (8). However, in vitro enzyme and human studies performed in the early 1980s showed that the NSAIDs ibuprofen and indomethacin can block aspirin inactivation of Cox-1 (9)(10)(11)(12). Very recently, a clinical study confirmed that ibuprofen does block platelet Cox-1 inhibition by low-dose aspirin, suggesting that that the coadministration of the two drugs may compromise the cardioprotective effect of aspirin (42).…”

Antinflammatory therapy and cardiovascular risk: a consensus view

“…I FANS, quali l'ibuprofen ed il naprossene ma non il diclofenac o il paracetamolo, interferiscono con l'azione cardioprotettiva dell'aspirina. Essi competono per il legame allo stesso canale ciclo-ossigenasico sulle piastrine impedendo, così, l'inibizione irreversibile della COX-1 piastrinica da parte dell'aspirina (6,(25)(26)(27)(28)(29). Per questo motivo, qualora sia necessaria un effetto antiaggregante piastrinico, la terapia con aspirina rimane necessaria anche in soggetti già in trattamento con FANS.…”