PHARMACOKINETICS OF 17-BETA-DIHYDROEQUILIN SULFATE AND 17-BETA-DIHYDROEQUILIN IN NORMAL POSTMENOPAUSAL WOMEN

The MCRs of 17 beta-dihydroequilin sulfate and 17 beta-dihydroequilin were determined in normal postmenopausal women by single iv injection of either 17 beta-[H-3]dihydroequilin sulfate ([H-3]17 beta-EqS) or 17 beta-[H-3]dihydroequilin ([H-3]17 beta-Eq). After the administration of [H-3]17 beta-EqS, blood was drawn at various time intervals, and th e plasma obtained was fractionated into the unconjugated, sulfate, and glucuronide fractions. The bulk of radioactivity was present in the s ulfate fraction, and from this [H-3]17 beta-EqS, [H-3]equilin sulfate, [H-3]equilenin sulfate, and 17 beta-[H-3]dihydroequilenin sulfate wer e isolated and purified, and their concentrations were measured. The d isappearance of [H-3]17 beta-EqS from plasma can be described as a fun ction of two exponentials. The half-life of the initial fast component was 5 +/- 0.2 min; this component represents the distribution and tra nsfer from a space, with a mean volume (V-1) of 6 +/- 0.5 L. The value for the rate constant (k) of total removal from this space was 300 +/ - 20 U/day, of which 35 +/- 2% was irreversible. The mean half-life of the slower component of 17 beta-EqS was 147 +/- 15 min, and the mean MCR was 376 +/- 93 L/day m(2). Similarly, after the administration of [H-3]17 beta-Eq, the disappearance of radioactivity as 17 beta-Eq from plasma also had two components. The half-lives of the fast and slow c omponent were 5.5 +/- 0.8 and 45 +/- 2.0 min, respectively. The MCR of 17 beta-Eq was 1252 +/- 103 L/day m(2), From both series of experimen ts, unconjugated and sulfate-conjugated equilin, equilenin, and 17 bet a-dihydroequilenin were isolated and purified, and their concentration s were measured. No 17 alpha-reduced metabolites were detected. These results indicate that 17 beta-EqS is cleared twice as fast as equilin sulfate (MCR, 176 L/day m(2)), whereas the more potent estrogen 17 bet a-Eq is cleared 2 times slower than equilin. The slower elimination an d greater estrogenic activity of 17 beta-Eq support the hypothesis tha t the major in vivo activity of equilin sulfate present in conjugated equine estrogen preparations is expressed via its metabolites 17 beta- EqS and 17 beta-Eq.