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Pharmacokinetics of 17ß-Dihydroequilin Sulfate in Normal Postmenopausal Women Under Steady State Conditions

Department of Obstetrics and Gynecology, Institute of Medical Sciences, University of Toronto, and St. Michael's Hospital, Toronto, Ontario, Canada; Department of Obstetrics and Gynecology, St. Michael's Hospital, Room 7-074 Bond Wing, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; bhavnani{at}smh.toronto.on.ca

Anthony Cecutti, MD

Alan Gerulath, MD

Department of Obstetrics and Gynecology, Institute of Medical Sciences, University of Toronto, and St. Michael's Hospital, Toronto, Ontario, Canada

Objective: In the present study, the constant infusion of [³H]17ß-dihydroequilin sulfate ([³H]17ß-EqS) was used to estimate the metabolic clearance rate (MCR) of 17ß-dihydroequilin sulfate (17ß-EqS) and to measure the conversion of this estrogen to equilin sulfate (EqS), equilenin sulfate (EqnS), 17ß-dihydroequilenin sulfate (17ß-Eqn) in normal postmenopausal women.

Methods: In seven healthy postmenopausal women, infusion of [³H]17ß-EqS was started 30 minutes after a priming dose and continued at a constant rate of 10-20 µCi/hour, for 3-6 hours. Three blood samples were taken during and at the end of infusion. From the plasma, unconjugated and sulfate-conjugated estrogens, 17ß-EqS, EqS, EqnS, 17ß-EqnS, Eq, Eqn, 17ß-Eq, and 17ß-Eqn were isolated and purified by high performance liquid chromatography. The MCR of 17ß-EqS and the conversion ratios and transfer constants (p) for precursor (17ß-EqS) to products were calcualted.

Results: The mean MCR of 17ß-EqS was calculated to be 797 ± 90 L/day or 506 ± 60 L/m² per day. The mean conversion ratio (CR^PRE-PRO_BB) was 2.4 ± 0.4 for EqS, 0.3 ± 0.04 for EqnS, 0.25 ± 0.03 for 17ß-EqnS, 0.09 ± 0.02 for Eq, 0.03 ± 0.01 for Eqn, 0.08 ± 0.02 for 17ß-Eq, and 0.03 ± 0.01 for 17ß-Eqn. In both the sulfate-conjugated and unconjugated forms, the most abundant metabolite formed was Eq. Based on the previously reported MCR of EqS (170 L/M² per day) and 17ß-Eq (1252 L/M² per day), the transfer constants []_BB were calculated to be 0.8 ± 0.10 and 0.20 ± 0.03, respectively. The results indicate that a large portion of 17ß-EqS is converted to EqS and the more potent estrogen 17ß-Eq. The ratio of EqS-17ß-EqS to 17ß-EqS-EqS was calculated to be 0.8 ± 0.1 and represents the extent of C-17-oxidation and reduction and indicates that substantial amounts of 17ß-reduced metabolites will still be presnet in the blood although the oxidation reaction was somewhat greater.

Conclusion: The data indicate that, compared with the classic estrogens, the in vivo metabolism of ring B unsaturated estrogens is complex. Thus, although the amount of 17ß-EqS originally present in the conjugated equine estrogens is small, the pharmacokinetics and pharmacodynamics of EqS, 17ß-EqS, and the extensive interconversions between these estrogens support the hypothesis that the major in vivo activity of the EqS present in conjugated equine estrogens is expresed through its metabolism to 17ß-EqS and 17ß-Eq. Furthermore, the increased estrogenic activity associated with this drug may in part be due to the formation of these 17ß-reduced metabolites.

Key Words: Conjugated equine estrogens • 17ß-dihydroequilin sulfate • equilin sulfate • ring B unsaturated estrogens • metabolic clearance rate • constant infusion

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