Louise P. Romanoff

Metabolism of the aromatase inhibitor 4-hydroxy-4-androstene-3,17-dione by male rhesus monkeys

Abstract Total radioactivity, unconjugated 4-hydroxy-4-androstene-3,17-dione (4-OHA) and unconjugated 4,17β-dihydroxy-4-androstene-3-one (4-OHT) were measured in whole blood 1–180 min after intravenous administration of [ 3 H]-4-OHA to two male rhesus monkeys. The MCR of 4-OHA was 1570 kg blood/day (1730 liters) in one and 790 and 885 kg blood/day (870 and 975 liters) blood/day in the other on two separate occasions. The respective CR BB 4-OHA,4-OHT were 0.13, 0.13 and 0.16. 4-OHA accounted for 6, 5.7 and 5.8% and 4-OHT for 0.78, 0.75 and 0.92% of the total blood radioactivity integrated from 1–180 min.

Synthesis of deuterium- and tritium-labeled 4-hydroxyandrostene-3,17-dione, an aromatase inhibitor, and its metabolism in vitro and in vivo in the rat

The metabolism of the aromatase inhibitor-4-hydroxyandrostenedione (4-OHA) was studied in vitro and in vivo in the rat. To accomplish this, deuterium- and tritium-labeled 4-OHA were prepared from 4-hydroxyandrosta-4, 6-dione-3,17-dione. The latter was synthesized from 4-androstene-3,17-dione. Using deuterated 4-OHA in in vitro incubations of rat ovarian microsomes, 4-hydroxytesterone (4-OHT) was identified by gas chromatography/mass spectroscopy as the major metabolite. 4-OHT constituted approximately 20% of the total radioactivity from [6,7-3H]-4-OHA in the ovarian microsomal incubations. Conversion of [6,7-3H]-4-OHA to 4-hydroxyesterone was approximately 0.1%. The major metabolite of [6, 7-3H]-4-OHA in vivo identified in the free, neutral fraction of rat blood was 3 beta-hydroxyandrostane-4,17-dione. The metabolite accounted for approximately 5% of the total radio-activity in the blood, Whereas 4-OHT accounted for only 0.1%, 4-OHT inhibited in vitro ovarian aromatization by 59%, but 3 beta-hydroxyandrostane-4-17-dione had little effect. It was concluded that the in vivo effects of 4-OHA previously reported are largely due to its own activity although additional effects of its metabolic products cannot be excluded.

Metabolism of progesterone-4-C14 in immature chimpanzees

Abstract Tracer doses of progesterone-4-C 14 were administered to four male and two female immature chimpanzees. An average of 28% of the radioactive dose was recovered in the urine in 48 hours. Twenty per cent of the dose of progesterone was extracted as unconjugated and glucuronidase-hydrolyzed metabolites of which the greater proportion was in the unconjugated form. An average of 7% of the dose of progesterone was recovered as pregnanediol-3α,20α, which accounted for 33% of the radioactivity in the neutral extracts. Except for the high proportion of unconjugated metabolites in the chimpanzees, the metabolism of progesterone was very similar to that observed for men.

Quantification of urinary 3α,21-dihydroxy-5β-pregnan-20-one and 5-pregnene-3β, 20α-diol by mass fragmentography

Abstract A sensitive and accurate method is described for measuring urinary corticosteroids by gas chromatography-mass spectroscopy (GC-MS). Using single peak monitoring (mass fragmentography) and electron impact ionization, the acetates of 3α,21-dihydroxy-5β-pregnan-20-one (tetrahydrodeoxycorticoster-one) and 5-pregnene-3β,20α-diol were estimated with deuterio-acetate carriers as recovery markers. With this technique, the coefficient of variation did not exceed 3% for GC-MS analyses of the urinary corticosteroid samples by single peak monitoring. An evaluation of the trimethylsilyl ether derivatives of the two steroids by chemical ionization was also made. Secretion rates determined for deoxycorticos-terone derived from specific activities of urinary tetrahydrodeoxycorticosterone and excretion levels of 5-pregnene-3β,20α-diol were slightly lower than those obtained by other methods.