Theoretical mechanism for the gastrointestinal safety of etodolac: Selective sparing of cytoprotective prostaglandins

Abstract

The high concentrations of pro-inflammatory prostaglandins (PGs) produced in the joint during the initial stage of inflammation can be decreased by inhibiting their biosynthesis with nonsteroidal anti-inflammatory drugs (NSAIDs). The commonly encountered gastrointestinal intolerance in human subjects treated with NSAIDs is generally attributed to inhibition of PG synthesis in gastric mucosa, where the natural role of locally biosynthesized PGs is to protect the mucosa from necrosis upon exposure to noxious agents. The action of an ideal NSAID should therefore be tissue specific, i.e., it should inhibit PG formation at the sites of inflammation but not in gastric mucosa, where PGs are needed for cytoprotection. We believe that etodolac, a new, structurally distinct NSAID, meets this criterion, inhibiting PG synthesis in a tissue-specific fashion. Experimental data supporting this interpretation were obtained in rats by demonstrating that daily administration of orally effective anti-inflammatory doses of etodolac had no significant effect on gastric mucosal PGE2 or prostacyclin levels (measured as the stable metabolite, 6-keto-PGF1 alpha). In contrast, naproxen, piroxicam, and aspirin caused a statistically significant PG depletion. The results obtained in rats thus support the view that the favorable gastrointestinal safety profile of etodolac in human patients may be attributable to selective sparing of the cytoprotective PGs in gastric mucosa.