Pharmacokinetics and pharmacodynamics of a novel estrogen Delta(8)-estronein postmenopausal women and men

Recently a tenth equine estrogen, identified as the sulfate ester of Delta( 8)-estrone has been reported to be present in Premarin (a conjugated equine estrogen preparation), and because of its unique ring B unsaturated struct ure (conjugated double bond in the B ring), we have, in the present study, determined its pharmacokinetics in postmenopausal women and men, its intera ction with uterine estrogen receptors and its uterotropic activity. After t he administration of [C-14]Delta(8)-estrone, blood was drawn at various tim e intervals, and the plasma fractionated into the unconjugated sulfate and glucuronide fractions. The disappearance of radioactivity as Delta(8)-estro ne 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, respec tively. The mean metabolic clearance rate calculated (MCR), was 1711 +/- 25 2 1/d m(2). From the unconjugated fraction, Delta(8)-17 beta-estradiol was also isolated and identified. From the sulfate conjugated fraction, Delta(8 )-estrone sulfate and Delta(8)-17 beta-estradiol sulfate were isolated in a lmost equal amounts. No other metabolites of Delta(8)-estrone was detectabl e in the plasma. Both Delta(8)-estrone and Delta(8)-17 beta-estradiol bind with human endometrial and rat uterine estrogen receptors with high affinit y. The binding affinities of Delta(8)-17 beta-estradiol for human endometri al and rat uterine cytoplasmic receptors were 4 and 25 times higher than th ose of the parent estrogen Delta(8)-estrone, respectively. Administration o f Delta(8)-estrone and Delta(8)-17 beta-estradiol (2 mu g/100 g body weight ) to immature rats significantly (P < 0.05) increased the uterine weight co mpared to the controls. These data demonstrate that Delta(8)-estrone has es trogenic activity, and that it is further metabolized in man to a single mo re potent estrogen, Delta(8)-17 beta-estradiol. The extent of this activati on by 17 beta-reduction appears to be greater than that observed with other estrogens. Both estrogens circulate as sulfate conjugates and are very slo wly eliminated from the circulation. These data further suggest that Delta( 8)-estrone and its major metabolite Delta(8)-17 beta-estradiol can contribu te to the overall in vivo biological effects of Premarin. (C) 1998 Elsevier Science Ltd. All rights reserved.