Comparison of in vivo bioavailability of progestational agents into the rat uterus and liver and the effect of plasma protein binding

The in vivo bioavailabilities of three clinically available progestational agents were evaluated with a previously described rat model. With this model a single-injection, double-isotope technique was performed to calculate and compare the unidirectional extractions of progesterone, 19-nortestosterone, and medroxyprogesterone acetate into the rat uterus and liver. To assess the role of plasma protein binding in the extraction of these agents, steroids were presented in four different vehicles: (1) Ringer's solution, 0.1% bovine serum albumin; (2) Ringer's solution, 4% bovine serum albumin; (3) Ringer's solution, 0.8 mg/ml, alpha 1-acid glycoprotein; (4) human pregnancy serum. The results revealed that liver extraction always exceeded uterine extraction for each progestin, regardless of the vehicle, and that liver extraction was approximately 100% for all steroids. With regard to the uterus, when binding proteins were not present in the injectate, the extraction of the three steroids was similar; the uterine vasculature was relatively permeable to these progestins, and bovine serum albumin and alpha 1-acid glycoprotein had no major effect on the uptake into the uterus. However, when human pregnancy serum was in the injectate, the extractions of progesterone and 19-nortestosterone into the rat uterus were significantly diminished. In contrast, pregnancy serum had no effect on the uptake of medroxyprogesterone acetate into the uterus, with the extraction equal to that of Ringer's solution alone. This suggests that, regardless of potential binding proteins, medroxyprogesterone acetate displays greater bioavailability than that of the other progestogens studied.