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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 unmetabolized 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.

Peripheral plasma from five young women was analyzed for cyproterone acetate and ethinyl estradiol during a period of 96 hours duration after single oral intake of a coated tablet of DIANE (2 mg of cyproterone acetate + 50 micrograms of ethinyl estradiol), and during a treatment cycle of 21 days during which the formulation was given daily. Radioimmunoassays were utilized for quantifications. A maximum concentration of 11.0 +/- 3.4 ng of cyproterone acetate/ml plasma was found 1.6 +/- 0.6 hours after a single administration of DIANE. Postmaximal disposition took place in two phases with half-lives of 1.9 +/- 0.6 hours and 2.2 +/- 0.2 days. The maximum level of 0.08 +/- 0.03 ng of ethinyl estradiol/ml plasma was found 1.6 +/- 0.6 hours after such single administration. Following commencement of a daily oral intake of DIANE a steady state was reached by the 5th to 8th days, during which 24 hours after each dose cyproterone acetate concentrations were found to be 2.4 +/- 0.7 times higher than at the corresponding time after a single administration. Accordingly, after the first third of the 21 day treatment cycle an almost constant plasma level was reached indicating an equilibrium of intake and elimination. Except for a change in the mean terminal half life after multiple dosing, there was evidently no change in the kinetics of cyproterone acetate. No pointers to an accumulation of ethinyl estradiol upon daily administration of DIANE could be found.

This report describes the pharmacokinetics of levonorgestrel, gestodene, norethisterone and cyproterone acetate following subcutaneous administration of oily solutions in the rat, beagle dog and rhesus monkey. The plasma levels of the progestogens were measured by means of specific radioimmunoassays. Half-lives calculated for the disposition process of a particular metabolically unchanged drug in plasma revealed marked differences in different animal species. Furthermore, comparison of the different progestogens showed large variations in this parameter in all the animal species. It became obvious that there are physico-chemical properties as well as metabolic rate limitations effecting the release and elimination of synthetic progestogens administered in oily solution. The results are compared with the half-lives of these progestogens administered intravenously as reported previously. A prolongation of half-life as a result of the depot effect of subcutaneous administration was demonstrated for all the progestogens in the rat, the beagle dog and the rhesus monkey.

Cyproterone acetate was administered orally and intramuscularly to 5 male patients. The level of the active substance in plasma was monitored at intervals during the period of application using radioimmunoassay specific for cyproterone acetate. The areas under the drug level curves were similar after oral and intramuscular application of cyproterone acetate when taking into consideration the different doses used. Accordingly, cyproterone acetate is not dependent upon a "first-pass" effect. The bioavailability of the active substance was complete following oral application.

Previous studies have shown that "xenobiotic" compounds such as the environmental pollutant alpha-hexachlorocyclohexane (alpha-HCH) and the synthetic sex steroid cyproterone acetate (CPA) induce growth of rat liver by hypertrophy and hyperplasia. After withdrawal of the growth stimuli, liver hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver hyperplasia: hepatic hyperplasia persisted when induced by alpha-HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic hyperplasia induced by CPA in rats: about 30% of liver DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found. Glutamate-pyruvate transaminase and alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number. Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast, alpha-HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that alpha-HCH, CPA and nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)