PHARMACOLOGICAL PROTECTION OF NSAID-INDUCED INTESTINAL PERMEABILITY IN THE RAT - EFFECT OF TEMPO AND METRONIDAZOLE AS POTENTIAL FREE-RADICAL SCAVENGERS

Recently, NSAID-induced changes in both the structure and function of the distal intestine have been found to occur more frequently and with greater toxicological significance than previously thought. We have p reviously validated a suitable animal model to evaluate intestinal per meability changes using orally administered Cr-51-EDTA that correlates with intestinal ulceration. In this study we investigated the suitabi lity of metronidazole and the nitroxide stable free radical scavenger (tempo) as protective agents against NSAID-induced intestinal permeabi lity. Male Sprague-Dawley rats were dosed with two doses of metronidaz ole (50 mg/kg, 12 and 1 h pre-NSAID) or a single 100 mg/kg dose of tem po 1 h prior to NSAIDs. The urinary excretion of the orally administer ed marker Cr-51-EDTA was measured. Both tempo and metronidazole dramat ically reduced indomethacin (20 mg/kg) and flurbiprofen (10 mg/kg)-ind uced intestinal permeability. All the animals exposed to indomethacin alone died within 48-96 h and presented with histological evidence of drug-induced enteropathy, ulceration and frank peritonitis. Protection by tempo and metronidazole suggests that free radicals and/or bacteri a may be important mediators in the pathogenesis of intestinal mucosal damage induced by NSAIDs. Nitric oxide donor compounds used concomita ntly with NSAIDs may protect gastrointestinal tract.