Pharmacokinetics and pharmacodynamics of a novel estrogen delta8-estrone in postmenopausal women and men.

ABSTRACT

Recently a tenth equine estrogen, identified as the sulfate ester of delta8-estrone has been reported to be present in Premarin (a conjugated equine estrogen preparation), and because of its unique ring B unsaturated structure (conjugated double bond in the B ring), we have, in the present study, determined its pharmacokinetics in postmenopausal women and men, its interaction with uterine estrogen receptors and its uterotropic activity. After the administration of [14C]delta8-estrone, blood was drawn at various time intervals, and the plasma fractionated into the unconjugated sulfate and glucuronide fractions. The disappearance of radioactivity as delta8-estrone from plasma can be described as a function of two exponentials. The half-lives of the first and second components were 5+/-0.2 and 40.4 min, respectively. The mean metabolic clearance rate calculated (MCR), was 1711+/-252 l/d m2. From the unconjugated fraction, delta8-17beta-estradiol was also isolated and identified. From the sulfate conjugated fraction, delta8-estrone sulfate and delta8-17beta-estradiol sulfate were isolated in almost equal amounts. No other metabolites of delta8-estrone was detectable in the plasma. Both delta8-estrone and delta8-17beta-estradiol bind with human endometrial and rat uterine estrogen receptors with high affinity. The binding affinities of delta8-17beta-estradiol for human endometrial and rat uterine cytoplasmic receptors were 4 and 25 times higher than those of the parent estrogen delta8-estrone, respectively. Administration of delta8-estrone and delta8-17beta-estradiol (2 microg/100 g body weight) to immature rats significantly (P< 0.05) increased the uterine weight compared to the controls. These data demonstrate that delta8-estrone has estrogenic activity, and that it is further metabolized in man to a single more potent estrogen, delta8-17beta-estradiol. The extent of this activation by 17beta-reduction appears to be greater than that observed with other estrogens. Both estrogens circulate as sulfate conjugates and are very slowly eliminated from the circulation. These data further suggest that delta8-estrone and its major metabolite delta8-17beta-estradiol can contribute to the overall in vivo biological effects of Premarin.