Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women

Abstract

The pharmacokinetics and enterohepatic cycling of oestradiol have been studied after three oral, single-dose administrations of equimolar doses of oestradiol alone, oestradiol plus desogestrel and oestradiol valerate, in a 3-way cross-over mode in 18 healthy postmenopausal women. Oestradiol was readily absorbed and metabolized to oestrone, which reached much higher serum concentrations (140 pg mL-1) than its parent compound (35 pg mL-1). All three formulations had the same kinetic profile and were bioequivalent on testing. Noticeable first and second absorption phases were apparent from the oestradiol and oestrone serum concentration-time curves for all oestradiol formulations. The mean serum concentration-time curves of the metabolite oestrone (corrected for endogenous oestrone) showed a second maximum at approximately 25 h. By means of line feathering, serum concentration-time curves were constructed which belonged to the first, second and third phases of absorption. The maximum serum concentration, C(max), of the second absorption or recirculation of oestrone was 20% that of the first, and the C(max) of the third circulation was 50% that of the second. The areas under the serum-concentration-time curves (AUC) for the second and third recirculations were similar - each comprised 12-13% of the total AUC. The oral clearance values of the recirculations were constant (590 L h-1). Enterohepatic recirculation of endogenous compounds is aimed at maintaining a steady-state serum concentration for immediate use and hydrolysis in the target organs. It is concluded that exogenously added oestradiol and its metabolites follow the recirculation pathways of the endogenous oestrogen pool.