Pharmacokinetic study of uterine progesterone retention

Tritium-labeled progesterone was administered to mature female rate in the proestrous stage of three different routes, gastric intubation, subcutaneous injection, and uterine intraluminal instillation, to study the kinetics involved in the uptake and retention of radioactivity by the uterus and various other tissues. Progesterone was retained at a much higher level and for a more prolonged period in the rat uterus after uterine intraluminal instillation. Progesterone bioavailability to the uterus was 45 times higher by uterine intraluminal instillation than by either gastric intubation or subcutaneous injection. Progesterone absorption by the rat endometrium was extremely fast. The observed biphasic decrease of radioactivity from the uterine tissue was explained adequately by a pharmacokinetic model in which progesterone is assumed to be present in two compartments within the uterine tissue. The pharmacokinetic parameters showed that the progesterone biological half-life in the uterine tissue during the alpha-phase was about 6.5 min, while that in the beta-phase was about 230 min. Tritium-labeled progesterone was perfused through the uterine luminal cavity of the rat until a steady state was reached. The radioactivity was found to exist at a mush higher concentration in the uterine tissue than many other tissues studies. The amount of radioactivity retained by the uterine tissue under constant perfusion was adequately described by a pharmacokinetic equation derived from a two-compartment open model. The amount of progesterone residing in the uterine tissue may, thus, be predicted from this equation using the predetermined pharmacokinetic parameters. At the steady state, the observed experimental values were in close approximation with the predicted values. A cyclic change in the uptake and retention of progesterone by uterine tissues was observed with rats in different stages of estrous cycle. Long-term insertion of the "Uterine Progesterone System," however, did not cause any significant change in the uterine capacity for either the absorption or the retention of progesterone administered by the direct uterine intraluminal route. The levels of the nuclear receptors for estradiol-17beta and progesterone in the uterine tissues of rats were measured by a 3H-steroid exchange method in which the specific 3H-steroid binding sites were estimated after the addition of an excess amount of the same but nonlabeled steroid. A similar procedure was used for the quantification of the progesterone cytosol receptor in rat uterine tissue. The level of the uterine estradiol-17beta cytosol receptor was determined from the amount of 8S complex obtained after a sucrose gradient centrifugation. The highest amounts of estradiol-17beta and progesterone receptors were found in uterine nuclei and cytosol of animals in proestrous, followed by diestrus, estrus, and metestrus in that order. No significant changes in the levels of either nuclear or cytosol receptors for both hormones were observed in the uterine tissues of rats inserted "Uterine Progesterone Systems" for four to five weeks.