Kenneth I.H. Williams

The effects of synthetic estrogens on the metabolic clearance and production rates of estrone and estradiol.

Abstract The metabolic clearance rates (MCR) of estrone (1) and estradiol were determined by pulse injections and constant infusions of 3 H-estrone and 3 H-estradiol in seven women taking mestranol-containing compounds and in seven women taking ethinyl estradiol-containing compounds. These results were compared with the results previously obtained in our laboratory (2, 3, 4, 5) in comparable women not taking these compounds. In the women taking mestranol the mean (± SE) MCR for estradiol, 750 ± 600 1/day/m 2 , was similar to our normal mean value, 790 ± 30 1/day/m 2 . However, the mean MCR for estrone was less 1,010 ± 60 1/day/m 2 than that in normals 1,230 ± 30 1/day/m 2 . In the women taking ethinyl estradiol the mean MCR for estradiol, 1,070 ± 60 1/day/m 2 was significantly ( P 2 was not different from the normal. Using an immunoassay to measure the concentrations of estradlol and. estrone in plasma, the mean level of estradlol in mestranol users was 40 ± 7 Pg/ml and in ethinyl estradlol users 69 ± 4 pg/ml. The mean calculated production rate for estradlol in the mestranol users was 47 ± 8 μ g/day and in the ethinyl estradlol users was 120 ± 22 μ g/day. The mean calculated, production rates for estrone were 71 ± 12 and 93 ± 12 μ g/day in the respective groups. Thus while mestranol appears to have little effect on endogenous estrogen metabolism, the use of ethinyl estradiol appears to increase the MCR of estradlol, but not of estrone. The MCR of estradlol returns to the normal range when ethinyl estradlol is stopped.

Metabolism of radioactive 17α-ethynylestradiol by women

Data on the urinary excretion and subsequent fractionation of radioactivity derived from 67-tritiated-17alpha-ethinyl estradiol (tritiated EE) are presented. Tritiated EE was administered orally to 9 women. 17alpha-ethinyl estradiol 2-methoxy-17alpha-ethinyl estradiol 2 -hydroxy-17alpha-ethinyl estradiol 3-methyl ether and D-homoestradiol-1 7abeta were identified as urinary metabolites by reverse isotope dilution. The extent of D-homoannulation was much less than that reported previously with rabbits.(AUTHORS MODIFIED)

Metabolism of dimethyl sulfide, dimethyl sulfoxide, and dimethyl sulfone in the rabbit

Abstract The subcutaneous injection of either dimethyl sulfide or dimethyl sulfoxide leads to the excretion of dimethyl sulfoxide and dimethyl sulfone in the urine of rabbits and to the expiration of a malodorous material (presumably dimethyl sulfide). Dimethyl sulfone, however, is not reduced to either the sulfoxide or the sulfide but is excreted unchanged. Dimethyl sulfone is also found in the urine of untreated rabbits.

4-Hydroxyestrone: A new metabolite of estradiol-17β from humans☆

Abstract 4-Hydroxyestrone has been identified, by reverse isotope dilution, as a urinary metabolite after injection of a mixture of 4- 3 H- and 4- 14 C-estradiol-17β into a 23 year old woman and a 39 year old man. This new metabolite accounted for 1.1% of the - 14 C dose administered to the woman and 0.51% of the - 14 C dose administered to the man. 7.3% Of the 3 H dose was liberated into the body water pool of the woman and 6.1% into that of the man. The yields of radioactive estrone, estradiol-17β, estriol, 2-hydroxyestrone, 2-methoxyestrone and 2-hydroxyestrone 3-methyl ether were also measured in both the Ketodase and Glusulase hydrolyzed urinary fractions from both subjects.

The metabolism of radioactive 17α-ethynylestradiol 3-methyl ether (mestranol) by women

Abstract 6,7- 3 H-17α-Ethynylestradiol 3-methyl ether (Mestranol) was administered orally to three women. The excretion of radioactivity via the urine vas greater than that observed earlier for the related cyclopentyl ether (Quinestrol). 17α-EthynyJLestradiol vas identified as a urinary metabolite by reverse isotope dilution.

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 doubly labelled ethynylestradiol-3-cyclopentyl ether in women.

Abstract The metabolic fate of orally administered 17α-ethynylestradiol-3-cyclopentyl ether (EECPE) labelled with 3 H in the steroid nucleus and with 14 C in the cyclo-pentyl group has been studied in women in two independent laboratories. Radioactivity was excreted over a period of up to 127 days, and unchanged EECPE was recovered from fat at 2 and 3 days after ingestion. Substantial quantities of ethynylestradiol were identified in the processed urine by recrystallization with carrier. Three other urinary metabolites were detected; the least polar contained 3 H and 14 C but was not EECPE. This metabolite is probably present in the urine over the entire excretion period. The most polar metabolite contained only 3 H and was quantitatively prominent in urines from the first few days collections but disappeared from the excretion pattern with time. A metabolite of intermediate polarity increased in relative amount during the collection period.

Metabolism of 2-3H- and 4-14C-17α-Ethynylestradiol 3-methyl ether (mestranol) by women

Urinary metabolites of oral C-4 tritiated and carbon-14 labeled mestranol were determined in 4 women 2 of whom were taking Ortho-Novum 1/50 containing 50 mcg mestranol. Urine was collected for 5-7 days and assayed for radioactivity. Some fractions were pooled and hydrolyzed with beta-glucuronidase. Metabolites were purified by preparative silica gel plates counter-current distribution and repeated recrystalization. The urinary excretion was protracted and much of the dose was not accounted for. Only 1.7-3% of the tritium indicative of reactions at position C-4 appeared in body water. The release rate half life was 12-17 hours in 3 subjects and .75 hours in 1 subject. 4 de-ethylated metabolites estrone estradiol estriol and 2-hydroxyesterone were released but the extent of de-ethylation was no greater than 1-2% of the dose. The ethinyl matabolites ethinyl estradi ol (6.6 and 11.3% of total dose) 2-hydroxy-ethinyl estradiol (.64 and .7%) and mestranol (.7 and .32%) were identified from hydrolysates the first demonstration of conjugated 2-hydroxy-ethinyl estradiol and mestranol in urine from women. These results showed no gross differences in excretion of metabolites from women taking or not takin mestranol in oral contraceptives. Some interesting results of this study were: little metabolism at C-4 some conjugation at the 17-beta hydroxyl group and a very low recovery or hydroxyethinyl estradiol.

Dimethyl Sulfone Isolation from Cows’Milk.

Summary Dimethyl sulfone has been detected and isolated from pasteurized cowsmilk. The source of the sulfone is not yet known. Dimethyl sulfoxide was not detected.