Estramustine
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| Systematic (IUPAC) name |
| (17β)-17-Hydroxyestra-1(10),2,4-trien-3-yl bis(2-chloroethyl)carbamate |
| Clinical data |
| Trade names |
Emcyt |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a608046 |
| Licence data |
US FDA:link |
| Pregnancy cat. |
D (AU) X (US) |
| Legal status |
Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) |
| Pharmacokinetic data |
| Bioavailability |
75%[1] |
| Metabolism |
Hepatic to estradiol and estrone[1] |
| Half-life |
15-24 hours[1] |
| Excretion |
Faeces (2.9-4.8%)[1] |
| Identifiers |
| CAS number |
2998-57-4 Y |
| ATC code |
L01XX11 |
| PubChem |
CID 259331 |
| DrugBank |
DB01196 |
| ChemSpider |
227635 Y |
| UNII |
35LT29625A Y |
| KEGG |
D04066 Y |
| ChEBI |
CHEBI:4868 Y |
| ChEMBL |
CHEMBL1575 Y |
| Chemical data |
| Formula |
C23H31Cl2NO3 |
| Mol. mass |
440.403 g/mol |
SMILES
- ClCCN(C(=O)Oc1cc3c(cc1)[C@H]2CC[C@@]4([C@@H](O)CC[C@H]4[C@@H]2CC3)C)CCCl
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InChI
-
InChI=1S/C23H31Cl2NO3/c1-23-9-8-18-17-5-3-16(29-22(28)26(12-10-24)13-11-25)14-15(17)2-4-19(18)20(23)6-7-21(23)27/h3,5,14,18-21,27H,2,4,6-13H2,1H3/t18-,19-,20+,21+,23+/m1/s1 Y
Key:FRPJXPJMRWBBIH-RBRWEJTLSA-N Y
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| Y (what is this?) (verify) |
Estramustine (Emcyt, Estracit) is a antimicrotubule chemotherapy agent used to treat prostate cancer. It is a derivative of oestrogen (specifically, estradiol) with a nitrogen mustard-carbamate ester moiety. It has been withdrawn from a number of markets (Australia, Brazil, Ireland and Norway).[2]
Contents
- 1 Clinical uses
- 2 Adverse effects
- 2.1 Contraindications
- 2.2 Interactions
- 3 Mechanism of action
- 4 Pharmacokinetics
- 5 Synthesis
- 6 See also
- 7 References
- 8 External links
Clinical uses[edit]
Estramustine is indicated, in the US, for the palliative treatment of metastatic and/or progressive prostate cancer.[1] Whereas in the UK it is indicated for the treatment of unresponsive or relapsing prostate cancer.[3][4][5][6]
Adverse effects[edit]
Adverse effects by frequency:[1][3]
Very common (>10% frequency):
- Oedema
- Dyspnoea
- Nausea
- Diarrhoea
- Breast tenderness and enlargement
Common (1-10% frequency):
- Lethargy
- Insomnia
- Congestive heart failure
- Easy bruising
- Anorexia
- Vomiting
- Itchiness
- Dry skin
- Impotence
- Leg cramps
- Decreased testosterone
- Impaired liver function
- Blood clots and complications thereof (including stroke, heart attacks, pulmonary embolism and thrombophlebitis)
Rare (<0.1% frequency):
- Anaemia
- Leucopenia
- Thrombocytopenia
- Confusion
- Depression
- Headache
- Lethargy
- Muscle weakness
- Angiooedema, occurs most commonly when used in combination with ACE inhibitors.
Unlike other nitrogen mustards it seldom produces significant GI or haematologic toxicity such as myelosuppression,[4] the major drug toxicity-related cause of drug discontinuation is thromboembolism (blood clots).[7]
Contraindications[edit]
It is contraindicated when used in children, patients hypersensitive to estradiol or nitrogen mustards, those with peptic ulcer (an ulcer in the digestive tract), those with severely compromised liver function, those with weak heart muscle (also known as myocardial insufficiency) and those with thromboembolic disorders or complications related to fluid retention.[3]
Interactions[edit]
Oestrogen mimics like estramustine have been reported to increase the toxicity and therapeutic efficacy of tricyclic antidepressants like amitriptyline and imipramine.[3] Dairy products and other products containing calcium, aluminium and magnesium have been reported to reduce the absorption of estramustine from the gastrointestinal tract hence reducing bioavailability.[3] There may be an increased risk of angiooedema in those concurrently taking ACE inhibitors.[3]
Mechanism of action[edit]
Its therapeutic actions are believed to be related to its ability to depolymerising the microtubules (which it achieves by binding to microtubule associated proteins), this arrests prostate cancer cells in the G2/M phase of the cell cycle.[4][5][6] It is selectively taken up by prostate cells and hence produces minimal cytotoxic effects on healthy tissue.[4]
Pharmacokinetics[edit]
Estramustine is delivered as an oral capsule. It is readily taken up from the gastrointestinal tract and then rapidly dephosphorylated from estramustine phosphate to estramustine.[4] Estramustine is then partially oxidised to estromustine.[4] Some estramustine and estromustine undergoes hydrolysis at the ester bond in the liver to form estradiol, estrone and normustine.[4] Milk, calcium, aluminium and magnesium supplements may reduce bioavailability.[3]
Active metabolites of estramustine
| Estramustine |
Estromustine |
Estradiol |
Estrone |
Normustine |
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Synthesis[edit]
Estramustine can be prepared directly from estradiol.[8]
See also[edit]
- Estrogen ester
- Estradiol and estrogen
- Bendamustine
- Carmustine
References[edit]
- ^ a b c d e f "Emcyt (estramustine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 8 February 2014.
- ^ Sweetman, S, ed. (12 February 2013). "Estramustine Sodium Phosphate". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 8 February 2014.
- ^ a b c d e f g "Estracyt Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfizer Limited. 12 August 2013. Retrieved 8 February 2014.
- ^ a b c d e f g Perry, CM; McTavish, D (July 1995). "Estramustine Phosphate Sodium". Drugs & Aging 7 (1): 49–74. doi:10.2165/00002512-199507010-00006. PMID 7579781.
- ^ a b Bergenheim, AT; Henriksson, R (February 1998). "Pharmacokinetics and pharmacodynamics of estramustine phosphate.". Clinical pharmacokinetics 34 (2): 163–72. doi:10.2165/00003088-199834020-00004. PMID 9515186.
- ^ a b Simpson, D; Wagstaff, AJ (2003). "Estramustine Phosphate Sodium". American Journal of Cancer 2 (5): 373–390. doi:10.2165/00024669-200302050-00013.
- ^ Fizazi, K; Le Maitre, A; Hudes, G; Berry, WR; Kelly, WK; Eymard, JC; Logothetis, CJ; Pignon, JP; Michiels, S; Meta-analysis of Estramustine in Prostate Cancer (MECaP) Trialists' Collaborative, Group (November 2007). "Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data.". The lancet oncology 8 (11): 994–1000. doi:10.1016/S1470-2045%2807%2970284-X. PMID 17942366.
- ^ Fex, H. J.; Hogberg, K. B.; Konyves, I.; Kneip, O. J.; 1967, U.S. Patent 3,299,104
External links[edit]
- Emcyt prescribing information
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Estrogenics
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| Receptor |
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ER (α, β)
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GPER
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- Agonists: Estradiol
- Fulvestrant
- G-1
- Genistein
- Quercetin
- Tamoxifen
|
|
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Enzyme
(inhibitors) |
|
20,22-Desmolase
|
- 22-ABC
- 3,3′-Dimethoxybenzidine
- 3-Methoxybenzidine
- Aminoglutethimide
- Cyanoketone
- Danazol
- Etomidate
- Mitotane
- Trilostane
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17α-Hydroxylase,
17,20-Lyase
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- 22-ABC
- 22-Oxime
- Abiraterone
- Bifonazole
- Clotrimazole
- Cyanoketone
- Cyproterone
- Danazol
- Econazole
- Galeterone
- Gestrinone
- Isoconazole
- Ketoconazole
- L-39
- Liarozole
- LY-207,320
- MDL-27,302
- Miconazole
- Mifepristone
- Orteronel
- Pioglitazone
- Rosiglitazone
- Spironolactone
- Stanozolol
- SU-10,603
- TGF-β
- Tioconazole
- Troglitazone
- VN/87-1
- YM116
|
|
|
3β-HSD
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- 4-MA
- Azastene
- Cyanoketone
- Danazol
- Epostane
- Genistein
- Gestrinone
- Metyrapone
- Oxymetholone
- Pioglitazone
- Rosiglitazone
- Trilostane
- Troglitazone
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17β-HSD
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Aromatase
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- 1,4,6-Androstatriene-3,17-dione
- 4-Androstene-3,6,17-trione
- 4-Cyclohexylaniline
- 4-Hydroxytestosterone
- 5α-DHNET
- Abyssinone II
- Aminoglutethimide
- Anastrozole
- Ascorbic acid (Vitamin C)
- Atamestane
- Bifonazole
- CGP-45,688
- CGS-47,645
- Clotrimazole
- DHT
- Difeconazole
- Econazole
- Exemestane
- Fadrozole
- Fenarimol
- Finrozole
- Formestane
- Imazalil
- Isoconazole
- Ketoconazole
- Letrozole
- Liarozole
- MEN-11066
- Miconazole
- Minamestane
- Nimorazole
- NKS01
- ORG-33,201
- Penconazole
- Plomestane
- Prochloraz
- Propioconazole
- Pyridoglutethimide
- Rogletimide
- Rotenone
- Talarozole
- Testolactone
- Tioconazole
- Triadimefon
- Triadimenol
- Troglitazone
- Vorozole
- YM511
- Zinc
Note: 5α-reductase and 21-hydroxylase inhibitors may also affect estrogen levels as they prevent metabolism of estrogen steroid precursors.
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| Other |
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Endogenous
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- Estrogens: 5α-Androstane-3β,17β-diol
- DHEA
- Estetrol
- Estradiol
- Estriol
- Estrone
- Antiestrogens: 2-Hydroxyestrone
- 16-Hydroxyestrone
- Precursors: Cholesterol
- 22R-Hydroxycholesterol
- 20α,22R-Dihydroxycholesterol
- Pregnenolone
- 17-Hydroxypregnenolone
- Progesterone
- 17-Hydroxyprogesterone
- Cortodoxone/Deoxycortisol
- DHEA
- DHEA sulfate
- 16-Hydroxy-DHEA
- 16-Hydroxy-DHEA sulfate
- Androstenediol
- Androstenedione
- 16-Hydroxyandrostenedione
- Testosterone
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Indirect
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- Androgens/Antiandrogens (see here)
- Calcitriol (a form of Vitamin D)
- GnRH agonists/antagonists (see here)
- Gonadotropins//Antigonadotropins (see here)
- Plasma proteins (SHBG, ABP, Albumin)
- Progestogens/Antiprogestins (see here)
- Prolactin
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Procedures
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- Adrenalectomy
- Hypophysectomy
- Oophorectomy
- Orchiectomy
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