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

Abstract

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

Methods: In seven healthy postmenopausal women, infusion of [³H]17β-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, 17β-EqS, EqS, EqnS, 17β-EqnS, Eq, Eqn, 17β-Eq, and 17β-Eqn were isolated and purified by high performance liquid chromatography. The MCR of 17β-EqS and the conversion ratios and transfer constants (p) for precursor (17β-EqS) to products were calcualted.

Results: The mean MCR of 17β-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 17β-EqnS, 0.09 ± 0.02 for Eq, 0.03 ± 0.01 for Eqn, 0.08 ± 0.02 for 17β-Eq, and 0.03 ± 0.01 for 17β-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 17β-Eq (1252 L/M² per day), the transfer constants [ρ]_BB were calculated to be 0.8 ± 0.10 and 0.20 ± 0.03, respectively. The results indicate that a large portion of 17β-EqS is converted to EqS and the more potent estrogen 17β-Eq. The ratio of ρEqS-17β-EqS to ρ17β-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 17β-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 17β-EqS originally present in the conjugated equine estrogens is small, the pharmacokinetics and pharmacodynamics of EqS, 17β-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 17β-EqS and 17β-Eq. Furthermore, the increased estrogenic activity associated with this drug may in part be due to the formation of these 17β-reduced metabolites.