Terminal half-lives in plasma and bioavailability of norethisterone, levonorgestrel, cyproterone acetate and gestodene in rats, beagles and rhesus monkeys☆

Abstract Norethisterone, levonorgestrel, cyproterone acetate and gestodene have been used for a long time in oral contraception and other indications, or are in the process of development for such indications. However, very little is known concerning the bioavailability and plasma levels of un-metabolized gestagens in the animal species used for chronic toxicity testing and pharmacological investigation. In this study the gestagens were administered intravenously, subcutaneously and orally to rats, beagles and rhesus monkeys. The drug plasma levels were determined by specific radioimmunoassay. The half-life of the terminal disposition phase was calculated following intravenous administration, and the extent of bioavailability was determined from the area under the drug level curves following subcutaneous and oral administration. The terminal half-lives of a particular compound in different animal species differed considerably. Furthermore, comparison of the different gestagens showed large variations in this parameter in all the animal species. In addition, inter-animal species comparison of a particular substance, and comparison of different substances in a single species, also showed great differences in bioavailability. The results are compared with the corresponding parameters in man. This investigation illustrates the fundamental problems inherent in the extrapolation of the results of toxicity studies and pharmacological investigations in animals, to man. The best tolerance and the lowest degree of pharmacological effect seem to occur where the bioavailability of a gestagen is poor and its terminal half-life short.