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 a nd to examine the effect of altered site of drug release using gastroduoden al and intestinal permeability tests in the vat model. Methods Adult male Sprague-Dawley mts were administered (n = 6 per group) either: ( 1) 100 mg/kg immediate or sustained release ibuprofen; (2) 100 mg/kg immedi ate release and ibuprofen lysinate; or (3) 100 mg/kg or 200 mg/kg ibuprofen po or sc. Upper and lower GI permeability as a surrogate marker of toxicit y were determined at pre-determined rimes using the urinary excretion of or ally administered sucrose and Cr-51-EDTA permeability probes, respectively. Results Ibuprofen administration resulted in a dose-dependent increase in both uppe r and lower permeability of the GI tract Both immediate and sustained relea se preparations of ibuprofen increased upper and lower GI permeability with no shift of toxicity to the site of drug release Ibuprofen lysinate also i nduced significant increased upper and lower GI permeability comparable to immediate release ibuprofen. Oral doses were not more toxic than sc doses. Conclusion Ibuprofen-induced increased GI permeably appears to be independent of the t ype of formulation and route of administration. This indicates that contrar y to some other nonstereoidal anti-inflammatory drugs, ibuprofen's effect o n GI permeability is mainly systemic and the direct local effect contribute s minimally to its overall CI toxicity Ibuprofen may be a suitable candidat e for sustained release formulations since its effect may be prolonged with out the danger of a shift of side effect from the upper to the lower GI tra ct