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 previously validated a suitable animal model to evaluate intestinal permeability changes using orally administered Cr-51-EDTA that correlates with intestinal ulceration. In this study we investigated the suitability of metronidazole and the nitroxide stable free radical scavenger (tempo) as protective agents against NSAID-induced intestinal permeability. Male Sprague-Dawley rats were dosed with two doses of metronidazole (50 mg/kg, 12 and 1 h pre-NSAID) or a single 100 mg/kg dose of tempo 1 h prior to NSAIDs. The urinary excretion of the orally administered marker Cr-51-EDTA was measured. Both tempo and metronidazole dramatically reduced indomethacin (20 mg/kg) and flurbiprofen (10 mg/kg)-induced 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 bacteria may be important mediators in the pathogenesis of intestinal mucosal damage induced by NSAIDs. Nitric oxide donor compounds used concomitantly with NSAIDs may protect gastrointestinal tract.