Defining the COX Inhibitor Selectivity of NSAIDs: Implications for Understanding Toxicity

Kathleen M Knights; Arduino A Mangoni; John O Miners


Expert Rev Clin Pharmacol. 2010;3(6):769-776. 

In This Article

Mechanisms of COX Inhibition by NSAIDs

All NSAIDs variably inhibit COX-1 and COX-2 and the mechanisms of inhibition fall into three broad categories, although there are exceptions. For example, nimesulide is a weak competitive inhibitor of COX-1 but a potent time-dependent inhibitor of COX-2, whereas celecoxib exhibits slow competitive binding and, at higher concentrations, binds irreversibly.[26] The three categories are:

  • Category 1: rapid competitive reversible binding of COX-1 and COX-2 (e.g., ibuprofen, piroxicam, mefenamic acid);

  • Category 2: rapid, lower-affinity reversible binding followed by time-dependent, higher-affinity, slowly reversible binding of COX-1 and COX-2 (e.g., diclofenac, flurbiprofen, indomethacin);

  • Category 3: rapid reversible binding followed by covalent modification of COX-1 and COX-2 (e.g., aspirin).[27,28]

Drugs such as ibuprofen competitively inhibit arachidonic acid binding and dissociate rapidly from the COX active site. By contrast, the slow tight-binding NSAIDs (e.g., flurbiprofen) initially compete poorly with arachidonic acid but then bind tightly in a time-dependent manner. Both ibuprofen and flurbiprofen adopt a similar conformation in the active site, and it is has been proposed that the kinetic differences between category 1 and 2 NSAIDs is the speed and efficiency by which they gain access through the narrow constriction in the COX channel created by Arg120, Tyr355 and Glu524.[29] The COX-2 inhibitors lack a carboxyl group and binding of these drugs within the COX active site does not require the charged interaction with Arg120. Instead, these larger methylsulfonylphenyl derivatives block the COX-2 channel in a time-dependent manner as the sulfonamide moiety slowly orientates within the hydrophobic side pocket. Simple competitive inhibition of COX-1 by COX-2 inhibitors is thought to occur because of lack of access to the side pocket.[7] Aspirin is unique in comparison with all the other NSAIDs. It orientates within the COX active site through a weak ionic bond with Arg120. This facilitates transacetylation of Ser530, which results in complete inhibition of COX activity. Clearly, such kinetic diversity in the mechanism of COX inhibition makes simple comparisons between NSAIDs of questionable validity and hence extrapolation of COX inhibition to cause–effect relationships tenuous.


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