Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full <i>in vitro</i> analysis

TLDR

NSAID benefits are linked to COX‑2 inhibition, while side effects stem from COX‑1 inhibition. The study aimed to compare classical NSAIDs and newer COX‑2‑selective drugs. Two human whole‑blood assays, including a modified version using A549 cells as a COX‑2 source, were employed. Analysis of over 40 NSAIDs and COX‑2‑selective agents showed that higher COX‑1 selectivity correlates with increased gastrointestinal toxicity, confirming COX‑1 inhibition as the underlying mechanism.

Abstract

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of &gt;40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.