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

Abstract

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.

Keywords::

• COX selectivity
• COX-1
• COX-2
• human whole blood assay
• IC₅₀ values
• in vitro models
• NSAIDs
• time-dependent inhibition

Financial & competing interests disclosure

John O Miners has received grants-in-aid from Pfizer Global Research and Astra Zeneca (Sodertalje) for research studies unrelated to this article. Kathleen M Knights has received a grant-in-aid from Pfizer Global Research for research studies unrelated to this article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.