PHARMACOKINETICS OF PROGESTERONE IN POSTMENOPAUSAL WOMEN - 1 - PHARMACOKINETICS FOLLOWING INTRAVAGINAL ADMINISTRATION

Progesterone was administered to postmenopausal women in a form of vag inal suppositories containing 100 and 200 mg active substance in Butyr um cacao (BC) and Massa estarinum (ME), a base with emulsifying proper ties. In the case of single doses, blood samples were taken at 2, 4, 6 , 24, 48 and 72 h. Another group;of patients received vaginal supposit ories (100 mg progesterone) once a day for a 6 day period, with blood samples taken 12 h after each administration. The plasma levels of pro gesterone were evaluated by radioimmunoassay. The time of maximum conc entration (t(max)) was 4 h in most cases, and 6 h in the others. The p lasma levels were not dose-proportional. Peak plasma concentrations we re in the range of 10-15 ng/ml with a mean of 10.5 ng/ml for the 100 m g and 12 ng/ml for the 200 mg doses. The ratio of the mean area under the curve (AUC) for 200 mg and the mean AUC for the 100 mg dose was fo und to be 1.37. Replacing BC with ME resulted in the lowering of c(max ) and AUC, and an increase in t(max) following a reducing in the rate and extent of adsorption. In the case of ME suppositories, the variabi lity in AUG, c(max) and t(max) was greater compared to that observed w ith the BC suppositories. Elimination half-time was in the range of 9- 10 h for BC and 14 h for ME suppositories. In vitro assessment of the release kinetics from a hydrophobic and an emulsion type base confirme d previous findings: the latter base assured better pharmaceutical ava ilability. The repeated doses did not seem to produce an accumulation of progesterone in the plasma. On the contrary, a small decrease in pl asma levels over time appeared during the 6 day period. Numerical anal ysis revealed an excellent goodness of fit for the in vivo experimenta l data via biexponential curves, i.e. a pseudomonocompartmental model.