Gastrointestinal damage demonstrated with nabumetone or etodolac in preclinical studies

Nabumetone, a nonacidic, nonsteroidal antiinflammatory drug (NSAID), and etodolac, an acidic NSAID, were compared to assess the gastrointestinal (GI) tolerability of these agents and their effects on gastric prostaglandins in rats. In a single-dose study, etodolac caused a significant increase in both gastric and intestinal damage 6, 24, 48, and 144 hours after dosing. In contrast, no significant GI damage was noted with nabumetone. Chronic, 28-day studies comparing five times the ID25 (the dose that reduces carrageenan-induced inflammation by 25% in 50% of animals) of nabumetone with twice the ID25 of etodolac demonstrated a significant increase in both gastric and intestinal damage with etodolac, but no GI damage with nabumetone, despite the higher dose employed. In single-dose studies comparing gastric damage and prostaglandin synthesis 4 hours after dosing, both nabumetone and etodolac did not significantly reduce gastric prostaglandin I2 production. However, there was a significant increase in gastric damage with etodolac, but not with nabumetone. It was hypothesized, and confirmed in a second study, that there is a transient inhibition of gastric prostaglandin synthesis with etodolac that is responsible, in part, for the gastric damage noted. In conclusion, acute and chronic dosing of nabumetone at doses up to five times the ID25 did not cause GI damage in rats. In contrast, etodolac did result in GI damage, which is thought to be, in part, the result of a transient inhibition of gastric prostaglandin synthesis, observed at minimally effective antiinflammatory doses.