The metabolism of mestranol, ethynylestradiol, norethynodrel, norethindrone, ethynodiol diacetate, lynestrenol, and norgestrel is reviewed. The estrogenic components of the oral contraceptives, mestranol or ethynylestradiol, have nearly identical metabolic pathways since mestranol is rapidly and almost completely converted to ethynylestradiol The major fraction of the drugs plus metabolites is excreted in the urine as conjugated materials. All of the 17beta-ethynyl progestins reviewed follow similar metabolic paths. For three of these, norethynodrel, ethynodiol diacetate and lynestrenol, a principal metabolite is norethindrone. Biotransformation to more polar metabolites and conjugation proceed rapidly for these three precursor drugs and norethindrone. Norgestrel follows metabolic paths similar to those of norethindrone. However, the ethyl moiety at the C-13 position appears to slow the metabolism of this steroid so that biotransformation to more polar metabolites and the conjugation of these steroids does not proceed as rapidly as that of the other progestins. The high progestational potency of norgestrel may be attributed to this slow rate of biotransformation. Some of the pharmacokinetic parameters derived from the research reports reviewed here are summarized. The compounds appear to be readily absorbed, and they and their metabolites are excreted to a greater extent in the urine than in the feces.

Chemical and histochemical analyses were carried out on uteri of four monkeys in which plastic IUDs or Cu-IUDs had been implanted for 36 to 43 days. The mean uterine copper content of the plastic-treated animals was 1.1 mug/gm (mean of two), while this value for the Cu-IUD treated monkeys was 1.7 mug/gm. The copper was distributed primarily in the cyclically renewed regions of the endometrium: the luminal fluid, endometrial surface, and superficial lamina propria. The element was localized and was not uniformly distributed in these regions. Copper analyses of plasma, liver, and kidney showed no differences between these two groups. Histopathologic evaluation revealed some areas of edema and increased numbers of neutrophils in plastic-IUD-treated animals. In the Cu-IUD-implanted monkeys, similar changes were observed as was a flattening of the surface epithelium. The endometrium had a loose areolar appearance. The copper elution rate was about 90 mug/day, about twice that observed in women using Cu-IUDs.

AbstractAus den Naphthyl‐oxocyclopentancarbonsäuren (Ia) und (Ib) entstehen bei der Behandlung mit Äthinylmagnesiumbromid (II) die Addukte (IIIa) bzw. (IIIb); neben (IIIa) wird das Lacton (IV) gebildet.

Human plasma metabolites of ethynodiol diacetate (3β,17β-diacetoxy-l7α-ethynyl-4-estrene) were identified by carrier addition analysis after oral administration of radiolabeled drug to a subject undergoing chronic treatment. Although a plasma half-life of 25 hours was observed for total radioactivity, the parent compound was not found 1 hour after administration. Carrier addition analysis showed the principal free plasma metabolite after 2 hours to be norethindrone (17α-ethvnyl-17 β-hydroxy-4-estren-3-one). Norethindrone was accompanied by its reduction products, 17α-ethynyl-5α-estrane-3α, 17β-diol and 17α-ethynyl-5β-estrane-3β,17β-diol. Two other isomeric reduction products of norethindrone, 17α-ethynyl-5β-estrane-3α, 17β-diol and 17α-ethvnyl-5α-estrane-3β,17β-diol, were also identified in the hydrolyzed plasma conjugate fraction, which made up the bulk of plasma radioactivity.

The disposition and metabolic fate of 14 C‐oxandrolone (17α‐methyl‐17β‐hydroxy‐2‐oxa‐5α‐androstan‐3‐one) has been studied in 6 healthy male subiects. After administration of a single oral dose (10 mg containing 20 p.Ci of 14C in ethanolic solution), the peak concentration of 14 C‐oxandrolone in the plasma was 417 (mean) µg per milliliter at 0.50 to 1.50 hours. Its level then declined in two phases: from 1.5 to 4.0 hours with a half‐life of 0.55 hour and from 4.0 to 48 hours with a half‐life of 9.4 hours. The ingested 14 C was eliminated predominantly by urinary excretion. In the urine, 43.6% of the administered 14 C was excreted in 24 hours and 60.4% in 96 hours. Recovery of 14 C in the feces accounted for only 2.8% of the dose. The chloroform extractable urinary radioactivity was largely composed of the unchanged drug, which accounted for 46.1 % of urinary 14 C or 28.7% of the illgested 14 C. Enzyme hydrolysis of the urinary coniugated fraction, which accounted for 31.3% of the urinary 14 C, gave two major aglycones in the approximate ratio of 2:7. These aglycones were tentatively identified as oxandrolone and 16β‐hydroxyoxandrolone, respectively.

The absorption, excretion, and biotransformation of 14C‐diphenoxylate hydrochloride (5 mg. containing 20.2 µc of 14C) when administered orally in ethanolic solution and without the presence of atropine sulfate was studied in 3 men. The mean urinary and fecal excretion of the total label in a 96 hour period was 13.65 ± 1.18 per cent and 49.20 ± 2.24 per cent, respectively. Thin‐layer radiochromatographic analysis of the label in excreta indicated extensive biotransformation of the parent drug. In the urine, the maior metabolites were characterized as diphenoxylic acid and hydroxydiphenoxylic acid. These acids were present in both the free and coniugated fractions. Radioactivity in the plasma was associated largely with diphenoxylic acid and to a smaller extent with the unchanged drug. Pharmacokinetic analysis using a one‐compartment open model showed a rapid absorption (t½ = 19.7 ± 1.7 minutes; peak level at 2.0 hours) of diphenoxylate followed by its rapid elimination (t½ = 2.50 ± 0.34 hours). The plasma half‐life (t½ = 4.38 ± 1.04 hours) of diphenoxylic acid was higher than that of diphenoxylate.

1. The metabolism of ethynodiol diacetate was investigated in four women. In seven days following oral administration, 58% dose was excreted in urine and 22% in faeces, predominantly in conjugated form. The urinary half-life was 15 h.2. Using a new and specific technique for isolation of ethynylated steroids involving pptn. of AgNO3 complexes, the less polar urinary metabolites identified were: norethindrone (3.6%, based on total urinary radioactivity), 17α-ethynyl-5β-estrane-3β,17β-diol (6.1%), 17α-ethynyl-5α-estrane-3α,17β-diol (1.1%), 17α-ethynyl-5β-estrane-3α, 17β-diol (0.4%), 17α-ethynyl-5α-estrane-3β,17β-diol (9.9%), and 17α-ethynyl-4,16-estradien-3-one (1.5%). No unchanged ethynodiol diacetate was found.3. Dehydration of the 17β-hydroxyl group to produce the last named metabolite appears to be a novel pathway.

1. The metabolism of norethynodrel was investigated in four women. In seven days following oral administration, 40% of the dose was excreted in the urine and 34% in the faeces, predominantly in conjugated form. The urinary half-life was 11 h.2. Fractionation of the urinary metabolites revealed a complex and extensive metabolic pattern. The metabolites isolated and identified from the less polar fractions were: 17α-ethynylestr-5(10)-ene-3α,17β-diol (1.8% total urinary radioactivity); 17α-ethynylestr-5(10)-ene-3β,17β-diol (4.7%); 17α-ethynyl-5β-estrane-3α,17β-diol (1.0%); and 17α-ethynyl-5α-estrane-3β,17β-diol (2.3%), unchanged norethynodrel was not isolated.

The biotransformation of disopyramide phosphate [4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide phosphate] was studied in rats and dogs using the 14C-labeled compound and in man using the unlabeled drug. Within 72 hr., 78.7 ± 1.4% of the administered radioactivity was recovered in the urine of dogs after oral administration and 44.1 ± 3.4% was recovered in the urine of rats after intraperitoneal administration. In dogs, 17.3 ± 3.4% of the urinary radioactivity was associated with the unchanged compound, 12.4 ± 1.6% with 4-isopropylamino-2-phenyl-2-(2-pyridyl)-butyramide, and 29.2 ± 2.6% with 3-phenyl-3-(2-pyridyl)-2-pyrrolidone; 18.0 ± 3.3% was present as a water-soluble conjugate which, on acid hydrolysis, gave the pyrrolidone as the major aglycone. In rats, the urinary radioactivity was predominantly (80.9 ± 2.3%) associated with the unchanged disopyramide. In this species the major metabolic pathway was aryl hydroxylation, giving two phenolic compounds, one of which was identified as 4-diisopropylamino-2-(p-hydroxyphenyl)-2-(2-pyridyl)butyramide. These phenolic metabolites were predominantly excreted in the bile as conjugates. In man, 56% of the administered drug was excreted unchanged in the urine while 4% was present as the secondary amine. The structural assignments of the metabolites were based on their detailed spectroscopic analysis and by comparison of their chromatographic properties with authentic samples.

The metabolism of intravenously administered radioactive potassium canrenoate (SC-14266-3H) was studied in three men. Within 5 days, 47.45 ± 4.17% of the administered radioactivity was recovered in urine and 14.36 ± 0.12% in the feces. In the urine, canrenone was identified as the major metabolite in the free fraction, and the major water-soluble metabolite was identified as the glucuronic acid ester conjugate of the hydroxy acid analog of SC-14266. The elimination of the total radioactivity in the plasma occurred in three phases, their half-lives being 0.073, 0.85, and 43.31 hr., respectively. The disappearance of the total label during the first and second phases was predominantly due to the excretion of the hydroxy acid derivative and canrenone. The third phase was a function of the excretion of the conjugate. Three hours after administration of the drug, the plasma levels of the hydroxy acid and canrenone were similar and declined, with a half-life of 8.25 hr.

The metabolism of sodium amylopectin sulfate (SN-263) has been studied in adult rats, 14C and 35S-labeled preparations being used. Previous studies have shown that this pepsin inhibitor is an effective antiulcer compound in experimental animals and in man. In the present study, the major fraction of the drug was excreted in the feces and exhibited a biological half-life of about 24 hours. A small amount of 35S appeared in the urine primarily as inorganic sulfate. It is concluded that the 35S that appeared in the urine was due not to absorption of the intact SN-263 molecule but to absorption of inorganic sulfate released by bacterial sulfatase activity in the large intestine. The 14C-labeled drug was excreted only in the feces; negligible amounts of 14C were detected in the urine or expired air. The compound was also found not to be absorbed in rats in which gastric ulcers had been induced by cortisol treatment.

An assay was devised in which the hypocholesterolemic action of parenterally administered androsterone could be demonstrated in rats given a low dose of propyl-thiouracil. Using this procedure an analogue of androsterone, 3α-methoxy-17α-methyl-5α-androstan-17-ol (SC-12790), was found to have an oral hypocholesterolemic activity similar to that of parenterally administered androsterone. Endocrine assays indicated the new steroid to be a weak androgen of the same order of potency as androsterone.

Analysis of the plasma of rats and patients treated with 20, 25-diazacholesterol dihydrochloride demonstrated the presence of desmosterol in the non-saponifiable lipids. Small amounts of 2 unidentified sterols were also detected in the human plasma samples.

22, 25-Diazacholestanol dihydrochloride, SC-11952, has been shown to be a potent hypocholesterolemic agent in the normal rat and in the rat made hypercholesterolemic with propylthiouracil. No obvious, acute, cardiovascular or central nervous side effects have been observed at doses as great as 10 times the minimal effective hypocholesterolemic dose. The compound does induce an accumulation in liver and plasma of desmosterol.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHypocholesterolemic Agents. III.1 N-Methyl-N-(dialkylamino)alkyl-17β-aminoandrost-5-en-3β-ol DerivativesR. E. Counsell, P. D. Klimstra, and R. E. RanneyCite this: J. Med. Chem. 1962, 5, 6, 1224–1233Publication Date (Print):November 1, 1962Publication History Published online1 May 2002Published inissue 1 November 1962https://pubs.acs.org/doi/10.1021/jm01241a014https://doi.org/10.1021/jm01241a014research-articleACS PublicationsRequest reuse permissionsArticle Views76Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options Get e-Alerts

This study was designed to further elucidate an estrone-parathyroid extract antagonism in bone. The incorporation of acetate-l-C14 into bone citrate was measured in the presence of both substances administered singly and in combination. Estrone increased bone citrate synthesis and concentration while parathyroid extract enhanced labeled citrate formation with little change in bone citrate concentration. When both materials were administered the results were essentially those observed for estrone alone although the changes were not as great.