ABSORPTION, DISTRIBUTION AND TOXICITY OF IBUPROFEN

The toxicity of ibuprofen, 2-(4-isobutylphenyl)propionic acid, a nonsteroidal agent with anti-inflammatory, analgesic, and antipyretic properties, was investigated in mice, rats, and dogs after single-dose oral or parenteral administration, and in rats and dogs after repeated oral administration for periods of up to 6 months. Ibuprofen induced gastrointestinal lesions, being more ulcerogenic in dogs than in rats; this difference in species susceptibility may well be related to the drug being more persistent in dog plasma. Organ weight changes occurring in rats were not associated with histologic abnormalities and were reversed when dosing ceased. Doses toxic to rats and rabbits were devoid of embryotoxic or teratogenic activity though ibuprofen or its metabolites entered the fetal circulation. Ibuprofen administered orally was rapidly absorbed in rats, rabbits, and dogs. Absorption in rats was shown to occur mainly from the intestine and to a lesser, though significant, extent from the stomach. Four metabolites of ibuprofen were detected in rabbit plasma, 3 of these also in rat plasma, but none in dog plasma. Distribution studies with ibuprofen-14C revealed that repeated oral dosing of rats led to some accumulation of radioactivity in the adrenals, ovaries, thyroid, skin, and fat, without structure or function being affected. Dogs, however, had high levels only in bile. © 1969.