Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone.

OBJECTIVES

To investigate the pharmacokinetics of progesterone, allopregnanolone and pregnanolone after treatment with a low oral dose of progesterone.

METHODS

Eight postmenopausal women were given a single oral dose of 20 mg of micronised progesterone on Day 1 and 20 mg twice daily on Days 2-7. Blood samples for the analysis of progesterone, allopregnanolone and pregnanolone were collected, and pharmacokinetic parameters were calculated.

RESULTS

After ingestion of a single dose, areas under the plasma concentration-time curve (AUC) from 0 to 12 h for progesterone, allopregnanolone and pregnanolone were 127%, 196% and 119% higher than the corresponding AUCs estimated to be caused by endogenous production. The maximum plasma concentration (Cmax) and the AUC values were significantly lower for pregnanolone than for progesterone and allopregnanolone. The trough concentrations at steady state (Css) were significantly higher than the baseline values, and Css for pregnanolone was significantly lower than for allopregnanolone and progesterone. Css for allopregnanolone was in the range of what is normally seen in the menstrual cycle.

CONCLUSIONS

After ingestion of a low-dose of progesterone, the concentrations of allopregnanolone were in the same range as those of progesterone. Oral doses of 20 mg of progesterone twice daily to postmenopausal women produced allopregnanolone concentrations comparable to those achieved physiologically in premenopausal women. Low-dose oral progesterone may be used as a prodrug to allopregnanolone when the aim is to investigate low-dose allopregnanolone effects in humans.