Estramustine phosphate

{{Short description|Chemical compound}} {{Distinguish|Estramustine}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = [(8''R'',9''S'',13''S'',14''S'',17''S'')-13-methyl-17-phosphonooxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthren-3-yl] ''N'',''N''-''bis''(2-chloroethyl)carbamate | image = Estramustine phosphate.svg | image_class = skin-invert-image | width = 250px | image2 = Estramustine phosphate molecule ball.png | image_class2 = bg-transparent | width2 = 250px

| tradename = Emcyt, Estracyt | Drugs.com = {{drugs.com|monograph|emcyt}} | MedlinePlus = a608046 | licence_US = Estramustine | pregnancy_AU = D | pregnancy_US = X | legal_AU = S4 | legal_CA = Rx-only | legal_US = Rx-only | legal_UK = POM | routes_of_administration = By mouth, IV | class = Chemotherapeutic agent; Estrogen; Estrogen ester

| bioavailability = 44–75% (as estramustine and estromustine)<ref name="pmid9515186" /> | protein_bound = • Estradiol: 98%<ref name="pmid16112947" /> • Estrone: 96%<ref name="pmid16112947" /> | metabolism = Liver, intestines<ref name="pmid11240822" /><ref name="pmid9515186" /><ref name="MSR">{{cite web|title=Emcyt (estramustine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 February 2014|url=http://reference.medscape.com/drug/emcyt-estramustine-342085#showall}}</ref> | metabolites = • Estramustine<ref name="pmid11240822" /><ref name="pmid9515186" /> • Estromustine<ref name="pmid11240822" /><ref name="pmid9515186" /> • Estradiol<ref name="pmid11240822" /><ref name="pmid9515186" /> • Estrone<ref name="pmid11240822" /><ref name="pmid9515186" /> • Phosphoric acid<ref name="pmid11240822" /><ref name="pmid9515186" /> • Normustine<ref name="Inoue2018" /> | elimination_half-life = • EMP: 1.27 hours<ref name="pmid7579781" /> {{Font|size=99%|• Estromustine: 10–14 hrs<ref name="pmid9515186" />}} • Estrone: 15–17 hours<ref name="pmid9515186" /> | excretion = Bile, feces (2.9–4.8%)<ref name="pmid9515186" /><ref name="MSR" />

| C=23 | H=32 | Cl=2 | N=1 | O=6 | P=1 | SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2OP(=O)(O)O)CCC4=C3C=CC(=C4)OC(=O)N(CCCl)CCCl | StdInChI_Ref = | StdInChI = 1S/C23H32Cl2NO6P/c1-23-9-8-18-17-5-3-16(31-22(27)26(12-10-24)13-11-25)14-15(17)2-4-19(18)20(23)6-7-21(23)32-33(28,29)30/h3,5,14,18-21H,2,4,6-13H2,1H3,(H2,28,29,30)/t18-,19-,20+,21+,23+/m1/s1 | StdInChIKey_Ref = | StdInChIKey = ADFOJJHRTBFFOF-RBRWEJTLSA-N }}  '''Estramustine phosphate''' ('''EMP'''), also known as '''estradiol normustine phosphate''' and sold under the brand names '''Emcyt''' and '''Estracyt''', is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men.<ref name="EmcytLabel">{{cite web |title = Emcyt estramustine phosphate sodium capsules | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018045s023lbl.pdf |website=FDA |access-date=14 March 2022 }}</ref><ref name="Inoue2018">{{cite book| vauthors = Inoue T |title=Hormone Therapy and Castration Resistance of Prostate Cancer|chapter=Role of Estramustine Phosphate and Other Estrogens for Castration-Resistant Prostate Cancer|year=2018|pages=249–256|publisher=Springer |doi=10.1007/978-981-10-7013-6_26|isbn=978-981-10-7012-9}}</ref><ref name="pmid27684806">{{cite journal | vauthors = Qin Z, Li X, Zhang J, Tang J, Han P, Xu Z, Yu Y, Yang C, Wang C, Xu T, Xu Z, Zou Q | display-authors = 6 | title = Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis | journal = Medicine | volume = 95 | issue = 39 | article-number = e4801 | date = September 2016 | pmid = 27684806 | pmc = 5265899 | doi = 10.1097/MD.0000000000004801 }}</ref><ref name="pmid21756277">{{cite journal | vauthors = Ravery V, Fizazi K, Oudard S, Drouet L, Eymard JC, Culine S, Gravis G, Hennequin C, Zerbib M | display-authors = 6 | title = The use of estramustine phosphate in the modern management of advanced prostate cancer | journal = BJU International | volume = 108 | issue = 11 | pages = 1782–1786 | date = December 2011 | pmid = 21756277 | doi = 10.1111/j.1464-410X.2011.10201.x | s2cid = 33456591 | doi-access = }}</ref><ref name="SimpsonWagstaff2003">{{cite journal | vauthors = Simpson D, Wagstaff AJ | title = Estramustine Phosphate Sodium | journal = American Journal of Cancer | year = 2003 | volume = 2 | issue = 5 | pages = 373–390 | doi = 10.2165/00024669-200302050-00013 | s2cid = 70507026 }}</ref><ref name="pmid11240822">{{cite journal | vauthors = Kitamura T | title = Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer | journal = International Journal of Urology | volume = 8 | issue = 2 | pages = 33–36 | date = February 2001 | pmid = 11240822 | doi = 10.1046/j.1442-2042.2001.00254.x | s2cid = 43384150 }}</ref><ref name="pmid9515186">{{cite journal | vauthors = Bergenheim AT, Henriksson R | title = Pharmacokinetics and pharmacodynamics of estramustine phosphate | journal = Clinical Pharmacokinetics | volume = 34 | issue = 2 | pages = 163–172 | date = February 1998 | pmid = 9515186 | doi = 10.2165/00003088-199834020-00004 | s2cid = 1943973 }}</ref><ref name="pmid9050135">{{cite journal | vauthors = Hudes G | title = Estramustine-based chemotherapy | journal = Seminars in Urologic Oncology | volume = 15 | issue = 1 | pages = 13–19 | date = February 1997 | pmid = 9050135 }}</ref><ref name="pmid7579781">{{cite journal | vauthors = Perry CM, McTavish D | title = Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer | journal = Drugs & Aging | volume = 7 | issue = 1 | pages = 49–74 | date = July 1995 | pmid = 7579781 | doi = 10.2165/00002512-199507010-00006 | s2cid = 36725810 }}</ref><ref name="pmid8595142">{{cite book | vauthors = Kreis W | title = Concepts, Mechanisms, and New Targets for Chemotherapy | chapter = Estramustine revisited | series = Cancer Treatment and Research | volume = 78 | pages = 163–184 | date = 1995 | publisher = Springer | pmid = 8595142 | doi = 10.1007/978-1-4615-2007-8_8 | isbn = 978-1-4613-5829-9 }}</ref> It is taken multiple times a day by mouth or by injection into a vein.<ref name="EmcytLabel" /><ref name="pmid27684806" /><ref name="pmid11240822" /><ref name="pmid9515186" /><ref name="pmid7579781" /><ref name="pmid8595142" />

Side effects of EMP include nausea, vomiting, gynecomastia, feminization, demasculinization, sexual dysfunction, blood clots, and cardiovascular complications.<ref name="pmid11240822" /><ref name="pmid21756277" /><ref name="pmid9274433" /> EMP is a dual cytostatic and hence chemotherapeutic agent and a hormonal anticancer agent of the estrogen type.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" /><ref name="pmid7579781" /> It is a prodrug of estramustine and estromustine in terms of its cytostatic effects and a prodrug of estradiol in relation to its estrogenic effects.<ref name="pmid9515186" /><ref name="pmid11240822" /> EMP has strong estrogenic effects at typical clinical dosages, and consequently has marked antigonadotropic and functional antiandrogenic effects.<ref name="Inoue2018" /><ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" />

EMP was introduced for medical use in the early 1970s.<ref name="pmid11240822" /> It is available in the United States, Canada, the United Kingdom, other European countries, and elsewhere in the world.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

==Medical uses== EMP is indicated, in the United States, for the palliative treatment of metastatic and/or progressive prostate cancer,<ref name="MSR" /> whereas in the United Kingdom it is indicated for the treatment of unresponsive or relapsing prostate cancer.<ref name="EMP-EMC">{{cite web|title=Estracyt Capsules - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Pfizer Limited|access-date=8 February 2014|date=12 August 2013|url=http://www.medicines.org.uk/emc/medicine/1511/SPC/Estracyt+Capsules/|archive-date=22 February 2014|archive-url=https://web.archive.org/web/20140222203824/http://www.medicines.org.uk/emc/medicine/1511/SPC/Estracyt+Capsules/}}</ref><ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="SimpsonWagstaff2003" /> The medication is usually reserved for use in hormone-refractory cases of prostate cancer, although it has been used as a first-line monotherapy as well.<ref name="pmid11240822" /> Response rates with EMP in prostate cancer are said to be equivalent to conventional high-dose estrogen therapy.<ref name="Lupulescu1990">{{cite book| vauthors = Lupulescu A |title=Hormones and Vitamins in Cancer Treatment|url=https://books.google.com/books?id=VddUa-2cp-YC&pg=PA40|date=24 October 1990|publisher=CRC Press|isbn=978-0-8493-5973-6|pages=40–}}</ref>

Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer.<ref name="Inoue2018" /> This is especially true in Western countries today.<ref name="Inoue2018" /> As a result, and also due to the scarce side effects of gonadotropin-releasing hormone modulators (GnRH modulators) like leuprorelin, EMP was almost abandoned.<ref name="pmid11240822" /> However, encouraging clinical research findings resulted in renewed interest of EMP for the treatment of prostate cancer.<ref name="pmid11240822" />

EMP has been used at doses of 140 to 1,400 mg/day orally in the treatment of prostate cancer.<ref name="StellaBorchardt2007">{{cite book| veditors = Stella V, Borchardt R, Hageman M, Oliyai R, Maag H, Tilley J |title=Prodrugs: Challenges and Rewards|url=https://books.google.com/books?id=qkjHxX5TgHEC&pg=PA174|date=12 March 2007|publisher=Springer Science & Business Media|isbn=978-0-387-49782-2|pages=174–}}</ref> However, oral EMP is most commonly used at a dose of 560 to 640 mg/day (280–320 mg twice daily).<ref name="pmid9515186" /> The recommended dosage of oral EMP in the Food and Drug Administration (FDA) label for Emcyt is 14 mg per kg of body weight (i.e., one 140 mg oral capsule for each 10 kg or 22 lbs of body weight) given in 3 or 4 divided doses per day.<ref name="EmcytLabel" /> The label states that most patients in studies of oral EMP in the United States have received 10 to 16 mg per kg per day.<ref name="EmcytLabel" /> This would be about 900 to 1,440 mg/day for a 90-kg or 200-lb man.<ref name="EmcytLabel" /> Lower doses of oral EMP, such as 280 mg/day, have been found to have comparable effectiveness as higher doses but with improved tolerability and reduced toxicity.<ref name="Inoue2018" /> Doses of 140 mg/day have been described as a very low dosage.<ref name="pmid20094950">{{cite journal | vauthors = Kitamura T, Suzuki M, Nishimatsu H, Kurosaki T, Enomoto Y, Fukuhara H, Kume H, Takeuchi T, Miao L, Jiangang H, Xiaoqiang L | display-authors = 6 | title = Final report on low-dose estramustine phosphate (EMP) monotherapy and very low-dose EMP therapy combined with LH-RH agonist for previously untreated advanced prostate cancer | journal = Aktuelle Urologie | volume = 41 | issue = Suppl 1 | pages = S34–S40 | date = January 2010 | pmid = 20094950 | doi = 10.1055/s-0029-1224657 | s2cid = 7710924 }}</ref> EMP has been used at doses of 240 to 450 mg/day intravenously.<ref name="pmid9515186" />

EMP and other estrogens such as polyestradiol phosphate and ethinylestradiol are far less costly than newer therapies such as GnRH modulators, abiraterone acetate, and enzalutamide.<ref name="Inoue2018" /><ref name="pmid14644018">{{cite journal | vauthors = Sayed Y, Taxel P | title = The use of estrogen therapy in men | journal = Current Opinion in Pharmacology | volume = 3 | issue = 6 | pages = 650–654 | date = December 2003 | pmid = 14644018 | doi = 10.1016/j.coph.2003.07.004 }}</ref><ref name="pmid10699602">{{cite journal | vauthors = Hedlund PO, Henriksson P | title = Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 Trial Study | journal = Urology | volume = 55 | issue = 3 | pages = 328–333 | date = March 2000 | pmid = 10699602 | doi = 10.1016/s0090-4295(99)00580-4 }}</ref> In addition, estrogens may offer significant benefits over other means of androgen deprivation therapy, for instance in terms of bone loss and fractures, hot flashes, cognition, and metabolic status.<ref name="Inoue2018" /><ref name="pmid10699602" />

EMP has been used to prevent the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.<ref name="pmid7541359">{{cite journal | vauthors = Shimizu TS, Shibata Y, Jinbo H, Satoh J, Yamanaka H | title = Estramustine phosphate for preventing flare-up in luteinizing hormone-releasing hormone analogue depot therapy | journal = European Urology | volume = 27 | issue = 3 | pages = 192–195 | date = 1995 | pmid = 7541359 | doi = 10.1159/000475159 }}</ref>

===Available forms=== EMP is or has been available in the form of both capsules (140 mg, 280 mg) for oral administration and aqueous solutions (300 mg) for intravenous injection.<ref name="StellaBorchardt2007" /><ref name="Muller1998">{{cite book| veditors = Muller NF, Dessing RP |title=European Drug Index: European Drug Registrations | edition = Fourth |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA245|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=245, 454}}</ref><ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA2153|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=2153–}}</ref><ref name="EmcytLabel" />

==Contraindications== EMP is contraindicated when used in children, patients hypersensitive to estrogens 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.<ref name="EMP-EMC" />

==Side effects== The side effects of EMP overall have been described as relatively severe.<ref name="pmid11240822" /> The most common side effects of EMP have been reported to be gastrointestinal side effects like nausea, vomiting, and diarrhea, with nausea and vomiting occurring in 40% of men.<ref name="pmid21756277" /><ref name="pmid9515186" /> They are usually mild or moderate in severity, and the nausea and vomiting can be managed with prophylactic antiemetic medications.<ref name="pmid21756277" /> Nonetheless, severe cases of gastrointestinal side effects with EMP may require dose reduction or discontinuation of therapy.<ref name="pmid9515186" /> Although nausea and vomiting have been reported to be the most common side effects of EMP, gynecomastia (male breast development) has been found to occur in as many as 83% of men treated with EMP, and the incidence of erectile dysfunction is possibly similar to or slightly less than the risk of gynecomastia.<ref name="pmid11240822" /> As a rule, feminization, a gynoid fat distribution, demasculinization, and impotence are said to occur in virtually or nearly 100% of men treated with high-dose estrogen therapy.<ref name="pmid9274433">{{cite journal | vauthors = Galbraith SM, Duchesne GM | title = Androgens and prostate cancer: biology, pathology and hormonal therapy | journal = European Journal of Cancer | volume = 33 | issue = 4 | pages = 545–554 | date = April 1997 | pmid = 9274433 | doi = 10.1016/S0959-8049(96)00444-3 }}</ref><ref name="pmid15663992">{{cite journal | vauthors = Tammela T | title = Endocrine treatment of prostate cancer | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 92 | issue = 4 | pages = 287–295 | date = November 2004 | pmid = 15663992 | doi = 10.1016/j.jsbmb.2004.10.005 | s2cid = 25425351 }}</ref> Decreased sexual activity has also been reported in men treated with EMP.<ref name="pmid9515186" /> These side effects are due to high estrogen levels and low testosterone levels.<ref name="pmid9515186" /><ref name="pmid11240822" /> Prophylactic irradiation of the breasts can be used to decrease the incidence and severity of gynecomastia with estrogens.<ref name="pmid9274433" />

Severe adverse effects of EMP are thromboembolic and cardiovascular complications including pulmonary embolism, deep vein thrombosis, stroke, thrombophlebitis, coronary artery disease (ischemic heart disease; e.g., myocardial infarction), thrombophlebitis, and congestive heart failure with fluid retention.<ref name="pmid21756277" /><ref name="pmid9515186" /> EMP produces cardiovascular toxicity similarly to diethylstilbestrol, but to a lesser extent in comparison at low doses (e.g., 280 mg/day oral EMP vs. 1 mg/day oral diethylstilbestrol).<ref name="pmid11240822" /><ref name="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | title = Estrogens in the treatment of prostate cancer | journal = The Journal of Urology | volume = 154 | issue = 6 | pages = 1991–1998 | date = December 1995 | pmid = 7500443 | doi = 10.1016/S0022-5347(01)66670-9 }}</ref> The prostate cancer disease state also increases the risk of thromboembolism, and combination with docetaxel may exacerbate the risk of thromboembolism as well.<ref name="pmid21756277" /> Meta-analyses of clinical trials have found that the overall risk of thromboembolism with EMP is 4 to 7%, relative to 0.4% for chemotherapy regimens without EMP.<ref name="pmid21756277" /><ref name="pmid15536625" /> Thromboembolism is the major toxicity-related cause of discontinuation of EMP.<ref name="pmid17942366">{{cite journal | vauthors = Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard JC, Logothetis CJ, Pignon JP, Michiels S | display-authors = 6 | title = Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data | journal = The Lancet. Oncology | volume = 8 | issue = 11 | pages = 994–1000 | date = November 2007 | pmid = 17942366 | doi = 10.1016/S1470-2045(07)70284-X }}</ref> Anticoagulant therapy with medications such as aspirin, warfarin, unfractionated and low-molecular-weight heparin, and vitamin K antagonists can be useful for decreasing the risk of thromboembolism with EMP and other estrogens like diethylstilbestrol and ethinylestradiol.<ref name="pmid21756277" /><ref name="pmid25920994">{{cite journal | vauthors = Petrioli R, Roviello G, Fiaschi AI, Laera L, Bianco V, Ponchietti R, Barbanti G, Francini E | display-authors = 6 | title = Low-Dose Estramustine Phosphate and Concomitant Low-Dose Acetylsalicylic Acid in Heavily Pretreated Patients With Advanced Castration-Resistant Prostate Cancer | journal = Clinical Genitourinary Cancer | volume = 13 | issue = 5 | pages = 441–446 | date = October 2015 | pmid = 25920994 | doi = 10.1016/j.clgc.2015.03.004 }}</ref><ref name="Inoue2018" />

Adverse liver function tests are commonly seen with EMP, but severe liver dysfunction is rare with the medication.<ref name="pmid9515186" /> Central nervous system side effects are rarely seen with EMP, although enlarged ventricles and neuronal pigmentation have been reported in monkeys treated with very high doses of EMP (20–140 mg/kg/day) for 3 to 6 months.<ref name="pmid9515186" /> EMP does not appear to have cytostatic effects in normal brain tissue.<ref name="pmid9515186" /> In women treated with EMP in clinical studies, a few instances of minor gynecological hemorrhages have been observed.<ref name="pmid9515186" /> EMP is described as relatively well tolerated among cytostatic antineoplastic and nitrogen-mustard agents, rarely or not at all being associated with significant hematologic toxicity such as myelosuppression (bone marrow suppression), gastrointestinal toxicity, or other more marked toxicity associated with such agents.<ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="pmid6375076" /> In contrast to most other cytostatic agents, which often cause myelosuppression, leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count), EMP actually produces leukocytosis (increased white blood cell count) as a side effect.<ref name="pmid86404" /><ref name="pmid6349745" />

In a small low-dose study using 280 mg/day oral EMP for 150 days, tolerability was significantly improved, with gastrointestinal irritation occurring in only 15% of men, and there was no incidence of severe cardiovascular toxicity or deep vein thrombosis.<ref name="pmid11240822" /><ref name="Inoue2018" /> In addition, no other side effects besides slight transient elevated liver enzymes were observed.<ref name="pmid11240822" /> These findings suggest that lower doses of oral EMP may be a safer option than higher doses for the treatment of prostate cancer.<ref name="Inoue2018" /> However, a subsequent 2004 meta-analysis of 23 studies of thromboembolic events with EMP found substantial incidence of thromboembolic events regardless of dosage and no association of EMP dose with risk of these complications.<ref name="pmid15536625">{{cite journal | vauthors = Lubiniecki GM, Berlin JA, Weinstein RB, Vaughn DJ | title = Thromboembolic events with estramustine phosphate-based chemotherapy in patients with hormone-refractory prostate carcinoma: results of a meta-analysis | journal = Cancer | volume = 101 | issue = 12 | pages = 2755–2759 | date = December 2004 | pmid = 15536625 | doi = 10.1002/cncr.20673 | s2cid = 21465413 }}</ref>

==Overdose== There has been no clinical experience with overdose of EMP.<ref name="EmcytLabel" /> Overdose of EMP may result in pronounced manifestations of the known adverse effects of the medication.<ref name="EmcytLabel" /> There is no specific antidote for overdose of EMP.<ref name="EMP-EMC" /> In the event of overdose, gastric lavage should be used to evacuate gastric contents as necessary and treatment should be symptom-based and supportive.<ref name="EmcytLabel" /><ref name="EMP-EMC" /> In the case of dangerously low counts of red blood cells, white blood cells, or platelets, whole blood may be given as needed.<ref name="EMP-EMC" /> Liver function should be monitored with EMP overdose.<ref name="EMP-EMC" /> After an overdose of EMP, hematological and hepatic parameters should continue to be monitored for at least 6 weeks.<ref name="EmcytLabel" />

EMP has been used at high doses of as much as 1,260 mg/day by the oral route and 240 to 450 mg/day by intravenous injection.<ref name="pmid11240822" /><ref name="pmid9515186" />

== Interactions ==

EMP has been reported to increase the efficacy and toxicity of tricyclic antidepressants like amitriptyline and imipramine.<ref name="EMP-EMC" /> When products containing calcium, aluminium, and/or magnesium, such as dairy products like milk, various foods dietary supplements, and antacids, are consumed concomitantly with EMP, an insoluble chelate complex/phosphate salt between EMP and these metals can be formed, and this can markedly impair the absorption and hence oral bioavailability of EMP.<ref name="pmid11240822" /><ref name="pmid9515186" /><ref name="EMP-EMC" /> There may be an increased risk of angioedema in those concurrently taking ACE inhibitors.<ref name="EMP-EMC" />

==Pharmacology== ===Pharmacodynamics=== {{See also|Pharmacodynamics of estradiol}}

EMP, also known as estradiol normustine phosphate, is a combined estrogen ester and nitrogen mustard ester.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" /> It consists of estradiol, an estrogen, linked with a phosphate ester as well as an ester of normustine, a nitrogen mustard.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" /> In terms of its pharmacodynamic effects, EMP is a prodrug of estramustine, estromustine, and estradiol.<ref name="pmid9515186" /><ref name="pmid11240822" /> As a prodrug of estradiol, EMP is an estrogen and hence an agonist of the estrogen receptors.<ref name="pmid9515186" /><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> EMP itself has only very weak affinity for the estrogen receptors.<ref name="pmid9515186" /> The medication is of about 91% higher molecular weight than estradiol due to the presence of its C3 normustine and C17β phosphate esters.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Because EMP is a prodrug of estradiol, it may be considered to be a natural and bioidentical form of estrogen,<ref name="OettelSchillinger2012" /> although it does have additional cytostatic activity via estramustine and estromustine.<ref name="pmid9515186" /><ref name="pmid11240822" />

EMP acts by a dual mechanism of action: 1) direct cytostatic activity via a number of actions; and 2) as a form of high-dose estrogen therapy via estrogen receptor-mediated antigonadotropic and functional antiandrogenic effects.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012">{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA540|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=540–}}</ref> The antigonadotropic and functional antiandrogenic effects of EMP consist of strong suppression of gonadal androgen production and hence circulating levels of androgens such as testosterone; greatly increased levels of sex hormone-binding globulin and hence a decreased fraction of free androgens in the circulation; and direct antiandrogenic actions in prostate cells.<ref name="pmid6375076" /><ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="Inoue2018" /><ref name="pmid10076535">{{cite journal | vauthors = Wang LG, Liu XM, Kreis W, Budman DR | title = Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor | journal = Biochemical Pharmacology | volume = 55 | issue = 9 | pages = 1427–1433 | date = May 1998 | pmid = 10076535 | doi = 10.1016/S0006-2952(97)00657-6 | doi-access = free }}</ref><ref name="pmid2093302">{{cite journal | vauthors = Van Poppel H, Werbrouck PW, Baert L | title = Effect of estramustine phosphate on free androgens. A comparative study of the effect of orchiectomy and estramustine phosphate on free androgens in patients with prostatic cancer | journal = Acta Urologica Belgica | volume = 58 | issue = 4 | pages = 89–95 | date = 1990 | pmid = 2093302 }}</ref><ref name="pmid7190620">{{cite journal | vauthors = Karr JP, Wajsman Z, Kirdani RY, Murphy GP, Sandberg AA | title = Effects of diethylstilbestrol and estramustine phosphate on serum sex hormone binding globulin and testosterone levels in prostate cancer patients | journal = The Journal of Urology | volume = 124 | issue = 2 | pages = 232–236 | date = August 1980 | pmid = 7190620 | doi = 10.1016/S0022-5347(17)55383-5 }}</ref> The free androgen index with oral EMP has been found to be on average 4.6-fold lower than with orchiectomy.<ref name="pmid2093302" /> As such, EMP therapy results in considerably stronger androgen deprivation than orchiectomy.<ref name="pmid7190620" /> Metabolites of EMP, including estramustine, estromustine, estradiol, and estrone, have been found to act as weak antagonists of the androgen receptor ({{abbrlink|EC50|half-maximal effective concentration}} = 0.5–3.1 μM), although the clinical significance of this is unknown.<ref name="pmid12084341">{{cite journal | vauthors = Olson KB, Pienta KJ | title = Recent advances in chemotherapy for advanced prostate cancer | journal = Current Urology Reports | volume = 1 | issue = 1 | pages = 48–56 | date = May 2000 | pmid = 12084341 | doi = 10.1007/s11934-000-0035-z | s2cid = 31084737 }}</ref><ref name="pmid10076535" /><ref name="pmid11240822" /><ref name="pmid9515186" />

Extremely high levels of estradiol and estrone occur during EMP therapy.<ref name="pmid11240822" /><ref name="Inoue2018" /> The estrogenic metabolites of EMP are responsible for its most common adverse effects and its cardiovascular toxicity.<ref name="pmid9515186" /> EMP has been described as having relatively weak estrogenic effects in some publications.<ref name="pmid7579781" /><ref name="pmid6375076" /> However, it has shown essentially the same rates and degrees of estrogenic effects, such as breast tenderness, gynecomastia, cardiovascular toxicity, changes in liver protein synthesis, and testosterone suppression, as high-dose diethylstilbestrol and ethinylestradiol in clinical studies.<ref name="EmcytLabel" /><ref name="Inoue2018" /><ref name="pmid6375076" /><ref name="pmid7190620" /><ref name="pmid3092893">{{cite journal | vauthors = Daehlin L, Damber JE, von Schoultz B, Bergman B | title = The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma. A comparative study of oestrogen sensitive liver proteins, gonadotrophins and prolactin | journal = British Journal of Urology | volume = 58 | issue = 4 | pages = 412–416 | date = August 1986 | pmid = 3092893 | doi = 10.1111/j.1464-410X.1986.tb09095.x }}</ref> The notion that EMP has relatively weak estrogen activity may have been based on animal research, which found that EMP had 100-fold lower uterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans.<ref name="pmid3092893" /><ref name="Fredholm1974">Fredholm, B., Jensen, G., Lindskog, M., & Muntzing, J. (1974, January). Effects of estramustine phosphate (Estracyt) on growth of DMBA-induced mammary tumors in rats. In Acta Pharmacologica et Toxicologica (Vol. 35, pp. 28-28). 35 Norre Sogade, PO Box 2148, DK-1016 Copenhagen, Denmark: Munksgaard Int Publ Ltd.</ref>

The mechanism of action of the cytostatic effects of EMP is complex and only partially understood.<ref name="pmid9515186" /> EMP is considered to mainly be a mitotic inhibitor, inhibiting mechanisms involved in the mitosis phase of the cell cycle.<ref name="pmid9515186" /><ref name="Inoue2018" /> Specifically, it binds to microtubule-associated proteins and/or to tubulin and produces depolymerization of microtubules (Kd = 10–20 μM for estramustine), resulting in the arrest of cell division in the G2/M phase (specifically metaphase).<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid1545778" /> EMP was originally thought to mediate its cytostatic effects as a prodrug of normustine, a nitrogen mustard, and hence was thought to be an alkylating antineoplastic agent.<ref name="pmid11240822" /><ref name="SimpsonWagstaff2003" /><ref name="pmid7579781" /><ref name="OettelSchillinger2012" /> However, subsequent research has found that EMP is devoid of alkylating actions, and that the influence of EMP on microtubules is mediated by intact estramustine and estromustine, with normustine or estradiol alone having only minor or negligible effects.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="pmid6373212" /> As such, the unique properties of the estramustine and estromustine structures, containing a carbamate-ester bond, appear to be responsible for the cytostatic effects of EMP.<ref name="pmid9515186" /> In addition to its antimitotic actions, EMP has also been found to produce other cytostatic effects, including induction of apoptosis, interference with DNA synthesis, nuclear matrix interaction, cell membrane alterations, induction of reactive oxygen species (free oxygen radicals), and possibly additional mechanisms.<ref name="pmid9515186" /><ref name="Inoue2018" /> EMP has been found to have a radiosensitizing effect in prostate cancer and glioma cells, improving sensitivity to radiation therapy as well.<ref name="pmid9515186" />

The cytostatic metabolites of EMP are accumulated in tissues in a selective manner, for instance in prostate cancer cells.<ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="Inoue2018" /> This may be due to the presence of a specific estramustine-binding protein (EMBP) (Kd = 10–35 nM for estramustine), also known as prostatin or prostatic secretion protein (PSP), which has been detected in prostate cancer, glioma, melanoma, and breast cancer cells.<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid2682681">{{cite journal | vauthors = Tew KD, Stearns ME | title = Estramustine--a nitrogen mustard/steroid with antimicrotubule activity | journal = Pharmacology & Therapeutics | volume = 43 | issue = 3 | pages = 299–319 | date = 1989 | pmid = 2682681 | doi = 10.1016/0163-7258(89)90012-0 }}</ref> Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.<ref name="pmid7579781" /><ref name="Inoue2018" /><ref name="pmid9515186" />

EMP was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen moiety for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positive tumor cells.<ref name="Inoue2018" /><ref name="OettelSchillinger2012" /><ref name="pmid16112947" /> Consequentially, it was thought that EMP would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved efficacy and tolerability.<ref name="Inoue2018" /> However, subsequent research found that there is very limited and slow cleavage of the normustine ester and that EMP is devoid of alkylating activity.<ref name="Inoue2018" /><ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="pmid6375076" /> In addition, it appears that estramustine and estromustine may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP.<ref name="pmid9515186" /><ref name="pmid11240822" />

Extremely high, pregnancy-like levels of estradiol may be responsible for the leukocytosis (increased white blood cell count) that is observed in individuals treated with EMP.<ref name="pmid86404">{{cite journal | vauthors = Alexander NC, Hancock AK, Masood MB, Peet BG, Price JJ, Turner RL, Stone J, Ward AJ | display-authors = 6 | title = Estracyt in advanced carcinoma of the breast: a phase II study | journal = Clinical Radiology | volume = 30 | issue = 2 | pages = 139–147 | date = March 1979 | pmid = 86404 | doi = 10.1016/S0009-9260(79)80133-6 }}</ref><ref name="pmid6349745">{{cite journal | vauthors = Daponte D, Sylvester R, De Pauw M, Fryszman A, Smith RM, Smith PH | title = Change in white cell count during treatment of advanced cancer of the prostate with estramustine phosphate and with stilboestrol | journal = British Journal of Urology | volume = 55 | issue = 4 | pages = 408–412 | date = August 1983 | pmid = 6349745 | doi = 10.1111/j.1464-410X.1983.tb03333.x }}</ref> This side effect is in contrast to most other cytotoxic agents, which instead cause myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count).{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

====Antigonadotropic effects==== EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days.<ref name="pmid11240822" /> Similarly, a dosage of 70 mg/day EMP suppressed testosterone levels into the castrate range within 4 weeks.<ref name="pmid11240822" />

===Pharmacokinetics=== {{See also|Pharmacokinetics of estradiol}}

thumb|right|450px|class=skin-invert-image|Estradiol and testosterone levels during therapy with 280 mg/day oral EMP in men with prostate cancer (n = 11).<ref name="pmid11240822" />

{| class="wikitable floatright" |+ Pharmacokinetics of estromustine after a single dose of EMP in men with prostate cancer (n = 5) |- ! Parameter !! {{abbr|IV|intravenous injection}} 300 mg !! Oral 420 mg |- | {{abbr|Cmax|Peak levels}} || 506 ± 61 ng/mL || 362 ± 38 ng/mL |- | Tmax || 2.6 ± 0.4 hours || 2.2 ± 0.2 hours |- | {{abbr|t1/2|Elimination half-life}} || 10.3 ± 0.95 hours || 13.6 ± 3.09 hours |- | {{abbr|AUC0–32|Area-under-the-curve levels (total exposure)}} || 4.82 ± 0.62 || 2.88 ± 0.34 |- | Bioavailability || 100.0% || 43.7% ± 4.6% |- class="sortbottom" | colspan="3" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Sources:''' <ref name="pmid6375076" /> |}

{| class="wikitable floatright" |+ Levels of EMP metabolites during continuous therapy with 560 mg/day oral EMP in men |- ! Metabolite !! Plasma !! Ratio |- | Estramustine || 20,000–23,000 pg/mL || rowspan="2" | 1:9.6–9.8 |- | Estromustine || 191,000–267,000 pg/mL |- | Estradiol || 4,900–9,000 pg/mL || rowspan="2" | 1:9.4–11.8 |- | Estrone || 71,000–85,000 pg/mL |- class="sortbottom" | colspan="3" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Sources:''' <ref name="pmid6375076" /> |}

Upon oral ingestion, EMP is rapidly and completely dephosphorylated by phosphatases into estramustine during the first pass in the gastrointestinal tract.<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid7579781" /><ref name="CavalliKaye2009">{{cite book| veditors = Cavalli F, Kaye SB, Hansen HH, Armitage JO, Piccart-Gebhart M |title=Textbook of Medical Oncology | edition = Fourth |url=https://books.google.com/books?id=WdDKBQAAQBAJ&pg=PA442|date=12 September 2009|publisher=CRC Press|isbn=978-0-203-09289-7|pages=442–}}</ref> Estramustine is also partially but considerably oxidized into estromustine by 17β-hydroxysteroid dehydrogenases during the first pass.<ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="pmid8595142" /><ref name="pmid6673977">{{cite journal | vauthors = Gunnarsson O, Andersson SB, Johansson SA | title = The hydrolysis of estramustine phosphate; in vitro studies | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 8 | issue = 4 | pages = 395–402 | date = 1983 | pmid = 6673977 | doi = 10.1007/BF03188772 | s2cid = 22105700 }}</ref> As such, EMP reaches the circulation as estramustine and estromustine, and the major metabolite of EMP is estromustine.<ref name="pmid9515186" /><ref name="pmid8595142" /> A limited quantity of approximately 10 to 15% of estramustine and estromustine is further slowly metabolized via hydrolysis of the normustine ester into estradiol and estrone, respectively.<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid6375076" /> This reaction is believed to be catalyzed by carbamidases, although the genes encoding the responsible enzymes have not been characterized.<ref name="pmid9515186" /><ref name="pmid19735314" /><ref name="pmid15733111" /> The circulating levels of normustine formed from EMP are insignificant.<ref name="pmid6373212">{{cite journal | vauthors = Hauser AR, Merryman R | title = Estramustine phosphate sodium | journal = Drug Intelligence & Clinical Pharmacy | volume = 18 | issue = 5 | pages = 368–374 | date = May 1984 | pmid = 6373212 | doi = 10.1177/106002808401800502 | s2cid = 25303747 }}</ref><ref name="GateTew2011">{{cite book| vauthors = Gate L, Tew KD |title=Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures|chapter=Alkylating Agents|series=Cancer Growth and Progression |year=2011|pages=61–85|publisher=Springer |doi=10.1007/978-90-481-9704-0_4|isbn=978-90-481-9703-3}}</ref> Release of nitrogen mustard gas from normustine via cleavage of the carboxylic acid group has not been demonstrated and does not seem to occur.<ref name="pmid1545778" /><ref name="pmid6375076" />

The oral bioavailability of EMP is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of EMP.<ref name="pmid9515186" /> The oral bioavailability of EMP specifically as estramustine and estromustine is 44 to 75%, suggesting that absorption may be incomplete.<ref name="pmid9515186" /> In any case, there is a linear relationship between the oral dose of EMP and circulating levels of estramustine and estromustine.<ref name="pmid9515186" /> Consumption of calcium, aluminium, or magnesium with oral EMP can markedly impair its bioavailability due to diminished absorption from the intestines, and this may interfere with its therapeutic effectiveness at low doses.<ref name="pmid11240822" /><ref name="EMP-EMC" />

Following a single oral dose of 420 mg EMP in men with prostate cancer, maximal levels of estromustine were 310 to 475 ng/mL (475,000 pg/mL) and occurred after 2 to 3 hours.<ref name="pmid9515186" /> Estradiol levels with 280 mg/day oral EMP have been found to increase to very high concentrations within one week of therapy.<ref name="pmid11240822" /> In one study, levels of estradiol were over 20,000 pg/mL after 10 days, were about 30,000 pg/mL after 30 days, and peaked at about 40,000 pg/mL at 50 days.<ref name="pmid11240822" /> Another study found lower estradiol levels of 4,900 to 9,000 pg/mL during chronic therapy with 560 mg/day oral EMP.<ref name="pmid6375076" /> An additional study found estradiol levels of about 17,000 pg/mL with 140 mg/day oral EMP and 38,000 pg/mL with 280 mg/day oral EMP.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} The circulating levels of estradiol and estrone during EMP therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively.<ref name="Inoue2018" /><ref name="pmid6375076" /> Levels of estramustine and estradiol in the circulation are markedly lower than those of estromustine and estrone, respectively, with a ratio of about 1:10 in both cases.<ref name="pmid9515186" /><ref name="pmid6375076" /> Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-late pregnancy, which range from 5,000 to 40,000 pg/mL.<ref name="Abbott2009">{{cite web | title = Estradiol | date = November 2009 | url = http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf | work = Abbott Laboratories | access-date = 2018-09-20 | archive-date = 2021-11-27 | archive-url = https://web.archive.org/web/20211127070253/https://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf }}</ref> No unchanged EMP is seen in the circulation with oral administration.<ref name="pmid9515186" />

The pharmacokinetics of EMP are different with intravenous injection.<ref name="pmid9515186" /> Following a single intravenous injection of 300 mg EMP, levels of EMP were higher than those of its metabolites for the first 8 hours.<ref name="pmid9515186" /> This is likely due to the bypassing of first-pass metabolism.<ref name="pmid9515186" /> However, by 24 hours after the dose, unchanged EMP could no longer be detected in the circulation.<ref name="pmid9515186" /> The clearance of EMP from blood plasma is 4.85 ± 0.684 L/h.<ref name="pmid9515186" /> The volumes of distribution of EMP with intravenous injection were small; under a two-compartment model, the volume of distribution for the central compartment was 0.043 L/kg and for the peripheral compartment was 0.11 L/kg.<ref name="pmid9515186" /> The plasma protein binding of EMP is high.<ref name="pmid9515186" /> Estramustine is accumulated in tumor tissue, for instance prostate cancer and glioma tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively).<ref name="pmid9515186" /> Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively).<ref name="pmid9515186" /> Estramustine and estromustine appear to accumulate in adipose tissue.<ref name="pmid9515186" />

The elimination half-life of estromustine with oral EMP was 13.6 hours on average, with a range of 8.8 to 22.7 hours.<ref name="pmid9515186" /> Conversely, the elimination half-life of estromustine with intravenous injection was 10.3 hours, with a range of 7.36 to 12.3 hours.<ref name="pmid9515186" /> For comparison, the corresponding elimination half-lives of estrone were 16.5 and 14.7 hours for oral and intravenous administration, respectively.<ref name="pmid9515186" /> Estramustine and estromustine are mainly excreted in bile and hence in feces.<ref name="pmid9515186" /><ref name="pmid6375076" /> They are not believed to be excreted in urine.<ref name="pmid9515186" />

[[File:Estramustine phosphate metabolism.png|thumb|center|900px|class=skin-invert-image|Metabolism of oral estramustine phosphate in humans.<ref name="pmid7579781" /><ref name="pmid9515186 "/><ref name="pmid6375076">{{cite journal | vauthors = Gunnarsson PO, Forshell GP | title = Clinical pharmacokinetics of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 22–27 | date = June 1984 | pmid = 6375076 | doi = 10.1016/S0090-4295(84)80093-X }}</ref><ref name="pmid19735314">{{cite journal | vauthors = Ozeki T, Takeuchi M, Suzuki M, Kitamura T, Takayanagi R, Yokoyama H, Yamada Y | title = Single nucleotide polymorphisms of 17beta-hydroxysteroid dehydrogenase type 7 gene: mechanism of estramustine-related adverse reactions? | journal = International Journal of Urology | volume = 16 | issue = 10 | pages = 836–841 | date = October 2009 | pmid = 19735314 | doi = 10.1111/j.1442-2042.2009.02374.x | s2cid = 38350076 }}</ref><ref name="pmid15733111">{{cite journal | vauthors = Suzuki M, Muto S, Hara K, Ozeki T, Yamada Y, Kadowaki T, Tomita K, Kameyama S, Kitamura T | display-authors = 6 | title = Single-nucleotide polymorphisms in the 17beta-hydroxysteroid dehydrogenase genes might predict the risk of side-effects of estramustine phosphate sodium in prostate cancer patients | journal = International Journal of Urology | volume = 12 | issue = 2 | pages = 166–172 | date = February 2005 | pmid = 15733111 | doi = 10.1111/j.1442-2042.2005.01004.x | s2cid = 71166897 | doi-access = }}</ref>]]

==Chemistry== {{See also|Estrogen ester|List of estrogen esters#Estradiol esters|List of hormonal cytostatic antineoplastic agents}}

EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a synthetic estrane steroid and a derivative of estradiol.<ref name="Elks2014" /><ref name="IndexNominum2000" /> It is an estrogen ester; specifically, EMP is a diester of estradiol with a C3 normustine (nitrogen mustard–carbamate moiety) ester and a C17β phosphate ester.<ref name="Elks2014" /><ref name="IndexNominum2000" /> EMP is provided as the sodium or meglumine salt.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Muller1998" /> EMP is similar as a compound to other estradiol esters such as estradiol sulfate and estradiol valerate, but differs in the presence of its nitrogen mustard ester moiety.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Antineoplastic agents related to EMP, although none of them were marketed, include alestramustine, atrimustine, cytestrol acetate, estradiol mustard, ICI-85966, and phenestrol.<ref name="Elks2014" /><ref name="IndexNominum2000" />

Due to its hydrophilic phosphate ester moiety, EMP is a readily water-soluble compound.<ref name="Loftsson2014">{{cite book| vauthors = Loftsson T |title=Drug Stability for Pharmaceutical Scientists|url=https://books.google.com/books?id=dUzyAQAAQBAJ&pg=PA77|date=25 January 2014|publisher=Academic Press|isbn=978-0-12-411562-0|pages=77–}}</ref><ref name="Bernal1997">{{cite book| vauthors = Bernal S |title=Drug Resistance in Oncology|url=https://books.google.com/books?id=x9rL5HiTFTUC&pg=PA287|date=21 August 1997|publisher=CRC Press|isbn=978-1-4200-0209-6|pages=287–}}</ref><ref name="Murff2012">{{cite book| vauthors = Murff SJ |title=Safety and Health Handbook for Cytotoxic Drugs|url=https://books.google.com/books?id=CqIPtcoUiMMC&pg=PA89|date=20 February 2012|publisher=Government Institutes|isbn=978-1-60590-705-5|pages=89–}}</ref> This is in contrast to most other estradiol esters, which are fatty acid esters and lipophilic compounds that are not particularly soluble in water.<ref name="pmid16112947" /> Unlike EMP, estramustine is highly lipophilic, practically insoluble in water, and non-ionizable.<ref name="StellaBorchardt2007" /> The phosphate ester of EMP was incorporated into the molecule in order to increase its water solubility and allow for intravenous administration.<ref name="EmcytLabel" />

The molecular weight of EMP sodium is 564.3 g/mol, of EMP meglumine is 715.6 g/mol, of EMP is 520.4 g/mol, of estramustine is 440.4 g/mol, and of estradiol is 272.4 g/mol.<ref name="PubChem">{{cite web | title = Estramustine phosphate| url = https://pubchem.ncbi.nlm.nih.gov/compound/259329 | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> As a result of these differences in molecular weights, EMP contains about 52%, EMP sodium about 48%, and EMP meglumine about 38% of the amount of estradiol within their structures as does an equal-mass quantity of estradiol.<ref name="PubChem" />

==History== EMP was first synthesized in the mid-1960s and was patented in 1967.<ref name="pmid1545778">{{cite journal | vauthors = Punzi JS, Duax WL, Strong P, Griffin JF, Flocco MM, Zacharias DE, Carrell HL, Tew KD, Glusker JP | display-authors = 6 | title = Molecular conformation of estramustine and two analogues | journal = Molecular Pharmacology | volume = 41 | issue = 3 | pages = 569–576 | date = March 1992 | doi = 10.1016/S0026-895X(25)08962-X | pmid = 1545778 | url = http://molpharm.aspetjournals.org/content/41/3/569 | url-access = subscription }}</ref> It was initially developed for the treatment of breast cancer.<ref name="pmid9515186" /> The idea for EMP was inspired by the uptake and accumulation of radiolabeled estrogens into breast cancer tissue.<ref name="pmid9515186" /> However, initial clinical findings of EMP in women with breast cancer were disappointing.<ref name="pmid9515186" /> Subsequently, radiolabeled EMP was found to be taken up into and accumulated rat prostate gland, and this finding culminated in the medication being repurposed for the treatment of prostate cancer.<ref name="pmid9515186" /><ref name="pmid11240822" /> EMP was introduced for medical use in the treatment of this condition in the early 1970s, and was approved in the United States for this indication in 1981.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="FiggChau2010">{{cite book| vauthors = Figg WD, Chau CH, Small EJ | title = Drug Management of Prostate Cancer|url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA402|date=14 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=402–}}</ref> EMP was originally introduced for use by intravenous injection.<ref name="pmid6375076" /> Subsequently, an oral formulation was introduced, and the intravenous preparation was almost abandoned in favor of the oral version.<ref name="pmid6375076" />

==Society and culture==

===Generic names=== EMP is provided as the sodium salt for oral administration, which has the generic names ''estramustine phosphate sodium'' ({{abbrlink|USAN|United States Adopted Name}}) and ''estramustine sodium phosphate'' ({{abbrlink|BANM|British Approved Name}}, {{abbrlink|JAN|Japanese Accepted Name}}), and as the meglumine salt for intravenous administration, which has the generic name ''estramustine phosphate meglumine''.<ref name="Muller1998" /><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA502|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=502–503}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA406|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=406–407}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA114|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=114–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/estramustine.html|title = Estramustine Uses, Side Effects & Warnings}}</ref> The {{abbrlink|INNM|International Nonproprietary Name}} is ''estramustine phosphate''.<ref name="Elks2014" /> The name ''estramustine phosphate'' is a contraction of ''estradiol normustine phosphate''.<ref name="Elks2014" /><ref name="Drugs.com" /> EMP is also known by its former developmental code names ''Leo 299'', ''Ro 21-8837'', and ''Ro 21-8837/001''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Brand names=== EMP is most commonly marketed under the brand names Estracyt and Emcyt, but has also been sold under a number of other brand names, including Amsupros, Biasetyl, Cellmustin, Estramustin HEXAL, Estramustina Filaxis, Estranovag, Multosin, Multosin Injekt, Proesta, Prostamustin, and Suloprost.<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="Muller1998" />

===Availability=== {{See also|List of estrogens available in the United States}}

EMP is marketed in the United States,<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 29 January 2017 | url = https://www.accessdata.fda.gov/scripts/cder/daf/}}</ref> Canada, and Mexico under the brand name Emcyt, whereas the medication is marketed under the brand name Estracyt in the United Kingdom and elsewhere throughout Europe as well as in Argentina, Chile, and Hong Kong.<ref name="IndexNominum2000" /> It has been discontinued in a number of countries, including Australia, Brazil, Ireland, and Norway.<ref name="Martindale">{{cite book|title=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=12 February 2013|access-date=8 February 2014|url=http://www.medicinescomplete.com/mc/martindale/current/1832-c.htm|chapter=Estramustine Sodium Phosphate|editor=Sweetman, S|place=London, UK}}</ref>

==Research== EMP has been studied in the treatment of other cancers such as glioma and breast cancer.<ref name="pmid9515186" /> It has been found to slightly improve quality of life in people with glioma during the first 3 months of therapy.<ref name="pmid9515186" />

== References == {{Reflist}}

== Further reading == {{refbegin|30em}} * {{cite journal | vauthors = Tew KD | title = The mechanism of action of estramustine | journal = Seminars in Oncology | volume = 10 | issue = 3 Suppl 3 | pages = 21–26 | date = September 1983 | pmid = 6364362 }} * {{cite journal | vauthors = Hoisaeter PA, Bakke A | title = Estramustine phosphate (Estracyt): experimental and clinical studies in Europe | journal = Seminars in Oncology | volume = 10 | issue = 3 Suppl 3 | pages = 27–33 | date = September 1983 | pmid = 6364363 }} * {{cite journal | vauthors = Sandberg AA | title = Metabolic aspects and actions unique to Estracyt | journal = Seminars in Oncology | volume = 10 | issue = 3 Suppl 3 | pages = 3–15 | date = September 1983 | pmid = 6364364 }} * {{cite journal | vauthors = Haukaas SA | title = Immunological effects of diethylstilbestrol and estramustine phosphate | journal = Scandinavian Journal of Urology and Nephrology. Supplementum | volume = 83 | pages = 1–32 | date = 1984 | pmid = 6387896 }} * {{cite journal | vauthors = Hauser AR, Merryman R | title = Estramustine phosphate sodium | journal = Drug Intelligence & Clinical Pharmacy | volume = 18 | issue = 5 | pages = 368–374 | date = May 1984 | pmid = 6373212 | doi = 10.1177/106002808401800502 | s2cid = 25303747 }} * {{cite journal | vauthors = Sandberg AA | title = Metabolic parameters of Estracyt pertinent to its effects in prostatic cancer | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 11–21 | date = June 1984 | pmid = 6375075 | doi = 10.1016/S0090-4295(84)80092-8 }} * {{cite journal | vauthors = Gunnarsson PO, Forshell GP | title = Clinical pharmacokinetics of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 22–27 | date = June 1984 | pmid = 6375076 | doi = 10.1016/S0090-4295(84)80093-X }} * {{cite journal | vauthors = Forsgren B, Björk P | title = Specific binding of estramustine to prostatic proteins | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 34–38 | date = June 1984 | pmid = 6375077 | doi = 10.1016/S0090-4295(84)80095-3 }} * {{cite journal | vauthors = Kalland T, Haukaas SA | title = Immunologic effects of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 39–45 | date = June 1984 | pmid = 6375078 | doi = 10.1016/S0090-4295(84)80096-5 }} * {{cite journal | vauthors = Høisaeter PA | title = Mode of action of Emcyt | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 46–48 | date = June 1984 | pmid = 6375079 | doi = 10.1016/S0090-4295(84)80097-7 }} * {{cite journal | vauthors = Müntzing J, Gunnarsson K | title = Preclinical pharmacology and toxicology of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 6–10 | date = June 1984 | pmid = 6375082 | doi = 10.1016/S0090-4295(84)80091-6 }} * {{cite journal | vauthors = Slack NH, Murphy GP | title = Clinical toxicity and long-term results of Emcyt therapy for prostate cancer | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 73–77 | date = June 1984 | pmid = 6375085 | doi = 10.1016/S0090-4295(84)80103-X }} * {{cite journal | vauthors = Hedlund PO | title = Mode of action of estramustine phosphate in hormone dependent and hormone non-dependent prostate cancer | journal = Progress in Clinical and Biological Research | volume = 185A | pages = 197–202 | date = 1985 | pmid = 3898129 }} * {{cite journal | vauthors = Hedlund PO | title = Estracyt--mode of action and clinical experience | journal = Progress in Clinical and Biological Research | volume = 243B | pages = 215–219 | date = 1987 | pmid = 3309981 }} * {{cite journal | vauthors = Murphy GP | title = A current review of the clinical experience with Estracyt | journal = Progress in Clinical and Biological Research | volume = 243B | pages = 221–225 | date = 1987 | pmid = 3309982 }} * {{cite journal | vauthors = Forsgren B | title = Estramustine-binding protein in rat and human prostate | journal = Scandinavian Journal of Urology and Nephrology. Supplementum | volume = 107 | pages = 56–58 | date = 1988 | pmid = 3287598 }} * {{cite journal | vauthors = Tew KD, Stearns ME | title = Intracellular effects of estramustine (Estracyt/Emcyt) | journal = Progress in Clinical and Biological Research | volume = 303 | pages = 169–175 | date = 1989 | pmid = 2674983 }} * {{cite journal | vauthors = Tew KD, Stearns ME | title = Estramustine--a nitrogen mustard/steroid with antimicrotubule activity | journal = Pharmacology & Therapeutics | volume = 43 | issue = 3 | pages = 299–319 | date = 1989 | pmid = 2682681 | doi = 10.1016/0163-7258(89)90012-0 }} * {{cite journal | vauthors = Könyves I | title = Estramustine phosphate (Estracyt) in the treatment of prostatic carcinoma | journal = International Urology and Nephrology | volume = 21 | issue = 4 | pages = 393–397 | date = 1989 | pmid = 2693392 | doi = 10.1007/BF02559635 | s2cid = 9727646 }} * {{cite journal | vauthors = Benson R, Hartley-Asp B | title = Mechanisms of action and clinical uses of estramustine | journal = Cancer Investigation | volume = 8 | issue = 3–4 | pages = 375–380 | date = 1990 | pmid = 2207764 | doi = 10.3109/07357909009012056 }} * {{cite journal | vauthors = Van Poppel H, Baert L | title = The present role of estramustine phosphate in advanced prostate cancer | journal = Progress in Clinical and Biological Research | volume = 370 | pages = 323–341 | date = 1991 | pmid = 1924466 }} * {{cite journal | vauthors = Janknegt RA | title = Estramustine phosphate and other cytotoxic drugs in the treatment of poor prognostic advanced prostate cancer | journal = The Prostate. Supplement | volume = 4 | pages = 105–110 | date = 1992 | pmid = 1574449 | doi = 10.1002/pros.2990210516 | s2cid = 40562112 }} * {{cite journal | vauthors = Tew KD, Glusker JP, Hartley-Asp B, Hudes G, Speicher LA | title = Preclinical and clinical perspectives on the use of estramustine as an antimitotic drug | journal = Pharmacology & Therapeutics | volume = 56 | issue = 3 | pages = 323–339 | date = December 1992 | pmid = 1301594 | doi = 10.1016/0163-7258(92)90023-S }} * {{cite book | vauthors = Kreis W | title = Concepts, Mechanisms, and New Targets for Chemotherapy | chapter = Estramustine revisited | series = Cancer Treatment and Research | volume = 78 | pages = 163–184 | date = 1995 | publisher = Springer | pmid = 8595142 | doi = 10.1007/978-1-4615-2007-8_8 | isbn = 978-1-4613-5829-9 }} * {{cite journal | vauthors = Perry CM, McTavish D | title = Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer | journal = Drugs & Aging | volume = 7 | issue = 1 | pages = 49–74 | date = July 1995 | pmid = 7579781 | doi = 10.2165/00002512-199507010-00006 | s2cid = 36725810 }} * {{cite journal | vauthors = Hudes G | title = Estramustine-based chemotherapy | journal = Seminars in Urologic Oncology | volume = 15 | issue = 1 | pages = 13–19 | date = February 1997 | pmid = 9050135 }} * {{cite journal | vauthors = Bergenheim AT, Henriksson R | title = Pharmacokinetics and pharmacodynamics of estramustine phosphate | journal = Clinical Pharmacokinetics | volume = 34 | issue = 2 | pages = 163–172 | date = February 1998 | pmid = 9515186 | doi = 10.2165/00003088-199834020-00004 | s2cid = 1943973 }} * {{cite journal | vauthors = Kitamura T | title = Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer | journal = International Journal of Urology | volume = 8 | issue = 2 | pages = 33–36 | date = February 2001 | pmid = 11240822 | doi = 10.1046/j.1442-2042.2001.00254.x | s2cid = 43384150 }} * {{cite journal | vauthors = Ravery V, Fizazi K, Oudard S, Drouet L, Eymard JC, Culine S, Gravis G, Hennequin C, Zerbib M | display-authors = 6 | title = The use of estramustine phosphate in the modern management of advanced prostate cancer | journal = BJU International | volume = 108 | issue = 11 | pages = 1782–1786 | date = December 2011 | pmid = 21756277 | doi = 10.1111/j.1464-410X.2011.10201.x | s2cid = 33456591 | doi-access = }} * {{cite journal | vauthors = Qin Z, Li X, Zhang J, Tang J, Han P, Xu Z, Yu Y, Yang C, Wang C, Xu T, Xu Z, Zou Q | display-authors = 6 | title = Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis | journal = Medicine | volume = 95 | issue = 39 | article-number = e4801 | date = September 2016 | pmid = 27684806 | pmc = 5265899 | doi = 10.1097/MD.0000000000004801 }} {{refend}}

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