COMPARISON OF INDOMETHACIN AND NIMESULIDE, A SELECTIVE CYCLOOXYGENASE-2 INHIBITOR, ON KEY PATHOPHYSIOLOGIC STEPS IN THE PATHOGENESIS OF NONSTEROIDAL ANTIINFLAMMATORY DRUG ENTEROPATHY IN THE RAT

Background: The predicted gastrointestinal tolerability of specific cy clooxygenase-2 inhibitors could be due to either a lack of 'topical' i rritation and/or lack of effect on cyclooxygenase-1, Methods: Key path ophysiologic steps (in vitro and in vivo uncoupling, intestinal prosta noid levels (prostaglandin E, thromboxane B-2, and 6-keto-prostaglandi n F-1 alpha), intestinal permeability (Cr-51-ethylenediaminetetraaceti c acid), inflammation (faecal excretion of a granulocyte marker protei n), and ulcer counts) in enteropathy induced by nonsteroidal anti-infl ammatory drugs were assessed after administration of indomethacin, 10 mg/kg: and 15 (roughly equipotent), 30, and 60 mg/kg of the preferenti al cyclooxygenase-2 inhibitor nimesulide. Results: Indomethacin uncoup led oxidative phosphorylation at lower concentrations than nimesulide in vitro. Indomethacin was associated with electron microscopy changes suggestive of uncoupling in 60%-70% of enterocytes examined, whereas nimesulide affected 10%-30% of enterocytes, depending on the dose. Ind omethacin increased intestinal permeability and caused inflammation an d ulcers with 71%-96% reductions in prostanoid levels. Nimesulide at 1 5 mg/kg caused no damage, whereas 30 and 60 mg/kg nimesulide were asso ciated with significant decreases in mucosal prostanoids (46%-75%), bu t only the 60-mg/kg dose caused a transient increase in intestinal per meability. However, at none of the doses did nimesulide cause intestin al inflammation or ulcurs. Conclusions: These results endorse thr idea that selective cyclooxygenase-2 inhibitors may be associated with som e gastrointestinal tolerance due to their selectivity for cyclooxygena se-2, inhibiting cyclooxygenase-1 at only very high doses, and reduced topical irritation.