Medrogestone
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| Systematic (IUPAC) name | |
|---|---|
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6,17α-Dimethylpregna-4,6-diene-3,20-dione
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| Clinical data | |
| Trade names | Ayerluton, Colpro, Colpron, Colprone, Etogyn, Prothil[1] |
| Pregnancy category |
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| Routes of administration |
Oral |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 100%[2][3] |
| Protein binding | Albumin ("major proportion")[2] |
| Metabolism | Hepatic (hydroxylation and glucuronidation)[2] |
| Biological half-life | 34.9 ± 17.0 hours[4][5] |
| Excretion | Urine and feces (as metabolites) |
| Identifiers | |
| CAS Number | 977-79-7 |
| ATC code | G03DB03 (WHO) G03FB07 (WHO) (with estrogen) |
| PubChem | CID 9949848 |
| ChemSpider | 8125459 |
| UNII | 077DN93G5B  |
| KEGG | D04885 |
| Synonyms | Medrogesterone; AY-62022, NSC-123018, R-13615 |
| Chemical data | |
| Formula | C23H32O2 |
| Molar mass | 340.5 g/mol |
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Medrogestone (INN, USAN, BAN) (brand names Colpro, Colpron, Colprone), or metrogestone, also known as 6,17α-dimethyl-6-dehydroprogesterone, is a steroidal progestin that is used in hormone replacement therapy, in the treatment of breast and endometrial cancers, and in other conditions.[1][6][7] It was developed in the 1960s, and appears to have been marketed since at least 1966.[8] The drug is available widely throughout Europe, and is also marketed in Canada, Argentina, and Hong Kong, though notably not in the United States.[6] As of 2010, medrogestone is no longer available in Germany or Austria.[9]
Contents
Indications[edit]
In the past, medrogestone was used in the treatment of endometrial cancer and in some regimens for breast cancer, and, in men, for benign prostatic hyperplasia. It still finds use in the treatment of amenorrhea[10] and as the progestin component in certain forms of menopausal hormone replacement therapy.[11]
Contraindications[edit]
Intrahepatic cholestasis of pregnancy (acute or in history), vaginal bleeding of unknown origin, and severe diseases of the liver such as tumours are absolute contraindications for medrogestone. Relative contraindications include a history of jaundice or itching in pregnancy or gestational pemphigoid.[medical citation needed]
Pregnancy and lactation[edit]
Medrogestone is contraindicated during pregnancy because progestogens are associated with risks for the foetus in animals and humans.[12] Studies in pregnant rabbits have shown skeletal deformations under 3 mg medrogestone per kilogram body weight but not under 1 mg/kg.[medical citation needed] Typical therapeutic doses are between 0.1 and 0.25 mg/kg.
It is not known whether medrogestone passes into breast milk, but it is to be expected given its lipophilicity and studies with chemically related progestins.[12]
Adverse effects[edit]
Medrogestone seldom produces adverse effects, all of which are typical of progestogens. They include lack of appetite, nausea, headache, dizziness, and depression.[medical citation needed]
Overdose[edit]
The acute toxicity of the drug is low. Overdose causes only harmless side-effects such as nausea and vaginal bleeding.[12] The LD50 has been found to range between 500 mg/kg in dogs and over 3000 mg/kg in rats. Chronic toxicity has been examined in animals, but nothing but the typical adverse effects of progestogens, and reduction of prostatic weight in rhesus monkeys, have been found. Accidental intake of the drug, including in children, is not dangerous.[medical citation needed]
Pharmacology[edit]
Pharmacodynamics[edit]
The profile of medrogestone is similar to the natural hormone progesterone. It has pronounced progestogenic effects and opposes the proliferative effects of estrogen in the uterus, but lacks androgenic, estrogenic and glucocorticoid activity. It is described as a pure progestogen.[8] In extremely high doses it is an androgen antagonist (in 2,500-fold therapeutic doses[medical citation needed]) as well as an antigonadotropin.[12]
Pharmacokinetics[edit]
The drug is absorbed quickly and completely from the gut and reaches peak plasma concentrations after about one to four hours. Unlike many other steroids it binds neither to transcortin (corticosteroid-binding globulin, CBG, which binds progesterone[13]) nor to sex hormone-binding globulin (SHBG), but to albumin. Medrogestone itself cannot be excreted. The substance is hydroxylised and glucuronidised in the liver, and the resulting metabolites are eliminated via urine and faeces.[medical citation needed]
Interactions[edit]
Enzyme inducers such as barbiturates, phenylbutazone, phenytoin, ampicillin or tetracyclines are expected to reduce plasma concentrations of medrogestone, but no systematic research has been done.[12]
Chemical properties[edit]
Medrogestone is a steroid. More specifically, it is a derivative of pregna-4,6-diene structurally related to the progestin chlormadinone acetate and the antiandrogen cyproterone acetate. As is frequently found in other synthetic steroid hormones, medrogestone possesses a lipophilic group at position 6. However, in contrast to chlormadinone acetate and cyproterone acetate or to fluocinolone that contain a chlorine or fluorine respectively at position 6, medrogestone contains a methyl substituent at this position. The methyl in position 17 is unusual for a steroid, as many such drugs carry an oxygen atom in that position.
Synthesis[edit]
The oral activity of 17α-methyl progesterone has already been alluded to. This agent, which may well owe this property to the inhibition of metabolism in a manner analogous to the gonadal steroids, is not sufficiently potent in its own right to constitute a useful drug. Incorporation of known potentiating modifications yields the commercially available oral progestin medrogestone (4).
The preparation of the 6-Methyl-16-dehydropregnenolone acetate (1) precursor is covered on the Melengestrol (acetate) page.
Reduction of the conjugated 16,17 double bond of 6-methyl-16-dehydropregnenolone acetate by means of lithium in liquid ammonia leads initially to the 17 enolate ion,; this is alkylated in situ with methyl iodide. The now-familiar steric control asserts itself to afford the 17α-methyl compound,.
The acetate group is lost as a side reaction. In an interesting modification on the usual scheme, (3) is treated with aluminum isopropoxide and a ketone (Oppenauer conditions) as well as chloranil in a single reaction; the 4,6-diene, (medrogesterone), is obtained directly from this step.
See also[edit]
References[edit]
- ^ a b Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 759–760. ISBN 978-1-4757-2085-3.
- ^ a b c Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (December 2003). "Classification and pharmacology of progestins". Maturitas. 46 Suppl 1: S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641.
- ^ Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1 (sup1): 3–63. doi:10.1080/13697130500148875. PMID 16112947.
- ^ Stanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Reviews in Endocrine & Metabolic Disorders. 3 (3): 211–24. doi:10.1023/A:1020072325818. PMID 12215716.
Medrogestone The pharmacokinetics of medrogestone (5 mg dose) was studied in 12 Chinese young males who received a single oral dose of this drug [20]. The mean ± standard deviation Cmax was 8.21 ± 2.78 ng/ml and Tmax was 2.57 ± 1.02; the half-life of elimination was 34.9 ± 17.0 hours.
- ^ Lobo R, Crosignani P, Paoletti R, Bruschi F (6 December 2012). Women’s Health and Menopause: New Strategies — Improved Quality of Life. Springer Science & Business Media. pp. 142–. ISBN 978-1-4615-1061-1.
- ^ a b Swiss Pharmaceutical Society (January 2000). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 638–. ISBN 978-3-88763-075-1.
- ^ Morton I, Morton I, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 173–. ISBN 978-0-7514-0499-9.
- ^ a b Revesz C, Chappel CI (December 1966). "Biological activity of medrogestone: a new orally active progestin". Journal of Reproduction and Fertility. 12 (3): 473–87. doi:10.1530/jrf.0.0120473. PMID 4288903.
- ^ Jasek W, ed. (2006). Austria-Codex (in German). 1 (2006/2007 ed.). Vienna: Österreichischer Apothekerverlag. p. 1696. ISBN 3-85200-176-5.
- ^ Medrogestone at the US National Library of Medicine Medical Subject Headings (MeSH)
- ^ Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: the complete drug reference (36th ed.). London: Pharmaceutical Press. p. 2113. ISBN 978-0-85369-840-1.
- ^ a b c d e "Fachinformation zu Colpro" [Colpro summary of product characteristics] (in German). Open Drug Database. November 1997. Retrieved 15 August 2010.
- ^ Loose DS, Stancel GM (2006). "57. Estrogens and Progestins". In Laurence Brunton, John Lazo, Keith Parker. Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–73. ISBN 978-0-07-142280-2.
- ^ Deghenghi R, Revesz C, Gaudry R (May 1963). "New Synthesis and Structure Activity Relationship in the 17-Alkylated Progesterone Series". Journal of Medicinal Chemistry. 6 (3): 301–4. doi:10.1021/jm00339a019. PMID 14185989.
