Evaluation of gastrointestinal toxicity of ibuprofen using surrogate markers in rats: effect of formulation and route of administration.

OBJECTIVE To elucidate the mechanism of gastrointestinal (GI) toxicity of ibuprofen and to examine the effect of altered site of drug release using gastroduodenal and intestinal permeability tests in the rat model. METHODS Adult male Sprague-Dawley rats were administered (n = 6 per group) either: (1) 100 mg/kg immediate or sustained release ibuprofen; (2) 100 mg/kg immediate release and ibuprofen lysinate; or (3) 100 mg/kg or 200 mg/kg ibuprofen po or s.c. Upper and lower GI permeability as a surrogate marker of toxicity were determined at pre-determined times using the urinary excretion of orally administered sucrose and 51Cr-EDTA permeability probes, respectively. RESULTS Ibuprofen administration resulted in a dose-dependent increase in both upper and lower permeability of the GI tract. Both immediate and sustained release preparations of ibuprofen increased upper and lower GI permeability with no shift of toxicity to the site of drug release. Ibuprofen lysinate also induced significant increased upper and lower GI permeability comparable to immediate release ibuprofen. Oral doses were not more toxic than s.c. doses. CONCLUSION Ibuprofen-induced increased GI permeable appears to be independent of the type of formulation and route of administration. This indicates that, contrary to some other nonsteroidal anti-inflammatory drugs, ibuprofen's effect on GI permeability is mainly systemic and the direct local effect contributes minimally to its overall GI toxicity. Ibuprofen may be a suitable candidate for sustained release formulations since its effect may be prolonged without the danger of a shift of side effect from the upper to the lower GI tract.