Defining the COX inhibitor selectivity of NSAIDS: implications for understanding toxicity

The hypothesis that the anti-inflammatory activity of NSAIDs derives from COX inhibition is well established. It also underpins the accepted mechanism of the gastrointestinal and renal toxicity of NSAIDs. However, in terms of NSAID-induced cardiovascular toxicity, is COX inhibition then guilty by association? Multiple experimental models of COX-1/COX-2 inhibition have enabled ranking of the relative inhibitory activity of NSAIDs. Inhibition is expressed as an IC₅₀ value and the index of COX selectivity as the ratio of the IC₅₀ value for COX-2 and COX-1. These data informed the 'imbalance hypothesis that the cardiovascular risk of NSAIDs results from an imbalance in the detrimental actions of COX-1-derived thromboxane A₂ and the beneficial actions of COX-2-derived prostacyclin (PGI₂). Data derived from in vitro models used to generate NSAID IC₅₀ values are discussed in the context of the difficulties in defining COX selectivity and hence understanding the toxicity of NSAIDs in current clinical use.