Preclinical toxicology profile of misoprostol

Abstract

The toxicity of misoprostol has been extensively examined in a variety ofin vitro andin vivo studies. Preclinical studies evaluated acute and chronic toxicity, mutagenicity and carcinogenicity, and reproductive toxicity. Single oral dose studies in rodents and non-rodents indicate a safety margin of at least 500 to 1000 fold between lethal doses in animals and therapeutic doses in humans. Chronic toxicity studies (52 weeks) have been performed at daily oral doses of up to 300 and 9000 μg/kg body weight in dogs and rats, respectively. Rectal temperatures were increased at 100 and 300 μg/kg in dogs, and serum iron was increased at 9000 μg/kg in rats. Stomach weights were increased in dogs and rats in a dose-correlated manner related, at least in part, to an increase in the number of normal epithelial cells (gastric hyperplasia). When drug treatment was stopped rectal temperatures, serum iron and stomach weights reverted to normal. Electron microscope studies on hyperplastic tissue showed that the ultrastructure was not affected. Hyperostosis has been observed, mainly in female mice, following prolonged drug treatment at high doses. Histological studies of bone tissues of rats and dogs and radiological studies of long bones of dogs following chronic administration of misoprostol showed that bone development was normal in all respects. Mutagenicity studies were negative and misoprostol was not fetotoxic or teratogenic in rats at oral doses up to 10000 μg/kg body weight, or in rabbits at doses up to 1000 μg/kg body weight. An increased number of resorptions was seen at 1000 μg/kg body weight or higher in one rabbit and one rat study. Misoprostol was not carcinogenic in rats at doses up to 2400 μg/kg body weight/day over a 24 month period. Evaluation of a 21 month carcinogenicity study in mice with misoprostol at oral doses up to 16000 μg/kg body weight/day is in progress.