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| Clinical data | |
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| Trade names | Emcyt, Estracyt |
| Other names | EMP; Leo 299; NSC-89199; Ro 21-8837/001; Estradiol normustine phosphate; Estradiol 3-normustine 17β-phosphate; Estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608046 |
| License data | |
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| Routes of administration | By mouth,IV |
| Drug class | Chemotherapeutic agent;Estrogen;Estrogen ester |
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| Pharmacokinetic data | |
| Bioavailability | 44–75% (as estramustine and estromustine)[1] |
| Protein binding | • Estradiol: 98%[2] • Estrone: 96%[2] |
| Metabolism | Liver,intestines[3][1][6] |
| Metabolites | •Estramustine[3][1] •Estromustine[3][1] •Estradiol[3][1] •Estrone[3][1] •Phosphoric acid[3][1] •Normustine[4] |
| Eliminationhalf-life | • EMP: 1.27 hours[5] • Estromustine: 10–14 hrs[1] • Estrone: 15–17 hours[1] |
| Excretion | Bile,feces (2.9–4.8%)[1][6] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.023.193 |
| Chemical and physical data | |
| Formula | C23H32Cl2NO6P |
| Molar mass | 520.38 g·mol−1 |
| 3D model (JSmol) | |
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Estramustine phosphate (EMP), also known asestradiol normustine phosphate and sold under the brand namesEmcyt andEstracyt, is a dualestrogen andchemotherapy medication which is used in the treatment ofprostate cancer in men.[7][4][8][9][10][3][1][11][5][12] It is taken multiple times a dayby mouth or byinjection into a vein.[7][8][3][1][5][12]
Side effects of EMP includenausea,vomiting,gynecomastia,feminization,demasculinization,sexual dysfunction,blood clots, andcardiovascular complications.[3][9][13] EMP is a dualcytostatic and hencechemotherapeutic agent and ahormonal anticancer agent of theestrogen type.[1][3][14][5] It is aprodrug ofestramustine andestromustine in terms of its cytostatic effects and a prodrug ofestradiol in relation to itsestrogenic effects.[1][3] EMP has strong estrogenic effects at typical clinical dosages, and consequently has markedantigonadotropic and functionalantiandrogenic effects.[4][1][3][14]
EMP was introduced for medical use in the early 1970s.[3] It is available in theUnited States,Canada, theUnited Kingdom, otherEuropean countries, and elsewhere in the world.[15][16]
EMP is indicated, in theUnited States, for thepalliative treatment ofmetastatic and/or progressive prostate cancer,[6] whereas in theUnited Kingdom it is indicated for the treatment of unresponsive orrelapsing prostate cancer.[17][5][1][10] 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.[3]Response rates with EMP in prostate cancer are said to be equivalent to conventionalhigh-dose estrogen therapy.[18]
Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer.[4] This is especially true inWestern countries today.[4] As a result, and also due to the scarce side effects ofgonadotropin-releasing hormone modulators (GnRH modulators) likeleuprorelin, EMP was almost abandoned.[3] However, encouraging clinical research findings resulted in renewed interest of EMP for the treatment of prostate cancer.[3]
EMP has been used at doses of 140 to 1,400 mg/day orally in the treatment of prostate cancer.[19] However, oral EMP is most commonly used at a dose of 560 to 640 mg/day (280–320 mg twice daily).[1] The recommended dosage of oral EMP in theFood 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.[7] 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.[7] This would be about 900 to 1,440 mg/day for a 90-kg or 200-lb man.[7] Lower doses of oral EMP, such as 280 mg/day, have been found to have comparable effectiveness as higher doses but with improvedtolerability and reduced toxicity.[4] Doses of 140 mg/day have been described as a very low dosage.[20] EMP has been used at doses of 240 to 450 mg/day intravenously.[1]
EMP and other estrogens such aspolyestradiol phosphate andethinylestradiol are far less costly than newer therapies such as GnRH modulators,abiraterone acetate, andenzalutamide.[4][21][22] In addition, estrogens may offer significant benefits over other means ofandrogen deprivation therapy, for instance in terms ofbone loss andfractures,hot flashes,cognition, andmetabolic status.[4][22]
EMP has been used to prevent thetestosterone flare at the start ofGnRH agonist therapy in men with prostate cancer.[23]
| Route/form | Estrogen | Dosage | |
|---|---|---|---|
| Oral | Estradiol | 1–2 mg 3x/day | |
| Conjugated estrogens | 1.25–2.5 mg 3x/day | ||
| Ethinylestradiol | 0.15–3 mg/day | ||
| Ethinylestradiol sulfonate | 1–2 mg 1x/week | ||
| Diethylstilbestrol | 1–3 mg/day | ||
| Dienestrol | 5 mg/day | ||
| Hexestrol | 5 mg/day | ||
| Fosfestrol | 100–480 mg 1–3x/day | ||
| Chlorotrianisene | 12–48 mg/day | ||
| Quadrosilan | 900 mg/day | ||
| Estramustine phosphate | 140–1400 mg/day | ||
| Transdermal patch | Estradiol | 2–6x 100 μg/day Scrotal: 1x 100 μg/day | |
| IMTooltip Intramuscular orSC injection | Estradiol benzoate | 1.66 mg 3x/week | |
| Estradiol dipropionate | 5 mg 1x/week | ||
| Estradiol valerate | 10–40 mg 1x/1–2 weeks | ||
| Estradiol undecylate | 100 mg 1x/4 weeks | ||
| Polyestradiol phosphate | Alone: 160–320 mg 1x/4 weeks With oralEE: 40–80 mg 1x/4 weeks | ||
| Estrone | 2–4 mg 2–3x/week | ||
| IV injection | Fosfestrol | 300–1200 mg 1–7x/week | |
| Estramustine phosphate | 240–450 mg/day | ||
| Note: Dosages are not necessarily equivalent.Sources: See template. | |||
EMP is or has been available in the form of bothcapsules (140 mg, 280 mg) fororal administration andaqueous solutions (300 mg) forintravenous injection.[19][24][25][7]
EMP iscontraindicated when used in children, patientshypersensitive to estrogens ornitrogen mustards, those withpeptic ulcer (anulcer in thedigestive tract), those with severelycompromised liver function, those with weakheartmuscle (also known asmyocardial insufficiency) and those withthromboembolic disorders or complications related tofluid retention.[17]
Theside effects of EMP overall have been described as relatively severe.[3] The most common side effects of EMP have been reported to begastrointestinal side effects likenausea,vomiting, anddiarrhea, with nausea and vomiting occurring in 40% of men.[9][1] They are usually mild or moderate in severity, and the nausea and vomiting can be managed withprophylacticantiemetic medications.[9] Nonetheless, severe cases of gastrointestinal side effects with EMP may require dose reduction ordiscontinuation of therapy.[1] 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 oferectile dysfunction is possibly similar to or slightly less than the risk of gynecomastia.[3] As a rule,feminization, agynoid fat distribution,demasculinization, and impotence are said to occur in virtually or nearly 100% of men treated withhigh-dose estrogen therapy.[13][26] Decreasedsexual activity has also been reported in men treated with EMP.[1] These side effects are due to highestrogen levels and lowtestosterone levels.[1][3] Prophylacticirradiation of thebreasts can be used to decrease the incidence and severity of gynecomastia with estrogens.[13]
Severe adverse effects of EMP arethromboembolic andcardiovascular complications includingpulmonary embolism,deep vein thrombosis,stroke,thrombophlebitis,coronary artery disease (ischemic heart disease; e.g.,myocardial infarction),thrombophlebitis, andcongestive heart failure withfluid retention.[9][1] EMP produces cardiovascular toxicity similarly todiethylstilbestrol, but to a lesser extent in comparison at low doses (e.g., 280 mg/day oral EMP vs. 1 mg/day oral diethylstilbestrol).[3][27] The prostate cancer disease state also increases the risk of thromboembolism, and combination withdocetaxel may exacerbate the risk of thromboembolism as well.[9]Meta-analyses ofclinical trials have found that the overall risk of thromboembolism with EMP is 4 to 7%, relative to 0.4% for chemotherapy regimens without EMP.[9][28] Thromboembolism is the majortoxicity-related cause ofdiscontinuation of EMP.[29]Anticoagulant therapy with medications such asaspirin,warfarin, unfractionated and low-molecular-weightheparin, andvitamin K antagonists can be useful for decreasing the risk of thromboembolism with EMP and other estrogens likediethylstilbestrol andethinylestradiol.[9][30][4]
Adverseliver function tests are commonly seen with EMP, but severeliver dysfunction is rare with the medication.[1]Central nervous system side effects are rarely seen with EMP, althoughenlarged ventricles andneuronalpigmentation have been reported in monkeys treated with very high doses of EMP (20–140 mg/kg/day) for 3 to 6 months.[1] EMP does not appear to have cytostatic effects in normalbrain tissue.[1] In women treated with EMP in clinical studies, a few instances of minorgynecologicalhemorrhages have been observed.[1] EMP is described as relatively well tolerated among cytostatic antineoplastic and nitrogen-mustard agents, rarely or not at all being associated with significanthematologictoxicity such asmyelosuppression (bone marrow suppression), gastrointestinal toxicity, or other more marked toxicity associated with such agents.[5][1][31] In contrast to most other cytostatic agents, which often cause myelosuppression,leukopenia (decreasedwhite blood cell count), andneutropenia (decreasedneutrophil count), EMP actually producesleukocytosis (increased white blood cell count) as a side effect.[32][33]
In a small low-dose study using 280 mg/day oral EMP for 150 days, tolerability was significantly improved, with gastrointestinalirritation occurring in only 15% of men, and there was no incidence of severe cardiovascular toxicity or deep vein thrombosis.[3][4] In addition, no other side effects besides slight transientelevated liver enzymes were observed.[3] These findings suggest that lower doses of oral EMP may be a safer option than higher doses for the treatment of prostate cancer.[4] However, a subsequent 2004meta-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.[28]
There has been no clinical experience withoverdose of EMP.[7] Overdose of EMP may result in pronounced manifestations of the known adverse effects of the medication.[7] There is no specificantidote for overdose of EMP.[17] In the event of overdose,gastric lavage should be used to evacuate gastric contents as necessary and treatment should besymptom-based and supportive.[7][17] In the case of dangerously low counts ofred blood cells,white blood cells, orplatelets,whole blood may be given as needed.[17]Liver function should be monitored with EMP overdose.[17] After an overdose of EMP,hematological andhepatic parameters should continue to be monitored for at least 6 weeks.[7]
EMP has been used at high doses of as much as 1,260 mg/day by theoral route and 240 to 450 mg/day byintravenous injection.[3][1]
EMP has been reported to increase theefficacy andtoxicity oftricyclic antidepressants likeamitriptyline andimipramine.[17] When products containingcalcium,aluminium, and/ormagnesium, such asdairy products likemilk, variousfoodsdietary supplements, andantacids, are consumed concomitantly with EMP, aninsolublechelate complex/phosphatesalt between EMP and thesemetals can be formed, and this can markedly impair theabsorption and henceoralbioavailability of EMP.[3][1][17] There may be an increased risk ofangioedema in those concurrently takingACE inhibitors.[17]
EMP, also known as estradiol normustine phosphate, is a combinedestrogen ester andnitrogen mustardester.[1][3][14] It consists ofestradiol, anestrogen, linked with aphosphate ester as well as an ester ofnormustine, a nitrogen mustard.[1][3][14] In terms of itspharmacodynamic effects, EMP is aprodrug ofestramustine,estromustine, andestradiol.[1][3] As a prodrug of estradiol, EMP is an estrogen and hence anagonist of theestrogen receptors.[1][2] EMP itself has only very weakaffinity for the estrogen receptors.[1] The medication is of about 91% highermolecular weight than estradiol due to the presence of its C3 normustine and C17β phosphate esters.[35][15] Because EMP is a prodrug of estradiol, it may be considered to be anatural andbioidentical form of estrogen,[14] although it does have additional cytostatic activity via estramustine and estromustine.[1][3]
EMP acts by a dualmechanism of action: 1) direct cytostatic activity via a number of actions; and 2) as a form ofhigh-dose estrogen therapy via estrogen receptor-mediatedantigonadotropic and functionalantiandrogenic effects.[1][3][14] The antigonadotropic and functional antiandrogenic effects of EMP consist of strong suppression ofgonadalandrogenproduction and hence circulating levels of androgens such astestosterone; greatly increased levels ofsex hormone-binding globulin and hence a decreased fraction of free androgens in thecirculation; and direct antiandrogenic actions in prostate cells.[31][1][3][4][36][37][38] The free androgen index with oral EMP has been found to be on average 4.6-fold lower than withorchiectomy.[37] As such, EMP therapy results in considerably strongerandrogen deprivation than orchiectomy.[38] Metabolites of EMP, including estramustine, estromustine, estradiol, andestrone, have been found to act as weakantagonists of theandrogen receptor (EC50Tooltip half-maximal effective concentration = 0.5–3.1 μM), although the clinical significance of this is unknown.[39][36][3][1]
Extremely high levels of estradiol and estrone occur during EMP therapy.[3][4] The estrogenicmetabolites of EMP are responsible for its most common adverse effects and itscardiovasculartoxicity.[1] EMP has been described as having relatively weak estrogenic effects in some publications.[5][31] However, it has shown essentially the same rates and degrees of estrogenic effects, such asbreast tenderness,gynecomastia, cardiovascular toxicity, changes inliver protein synthesis, and testosterone suppression, as high-dosediethylstilbestrol andethinylestradiol in clinical studies.[7][4][31][38][40] The notion that EMP has relatively weak estrogen activity may have been based onanimal research, which found that EMP had 100-fold loweruterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans.[40][41]
The mechanism of action of thecytostatic effects of EMP is complex and only partially understood.[1] EMP is considered to mainly be amitotic inhibitor, inhibiting mechanisms involved in themitosis phase of thecell cycle.[1][4] Specifically, it binds tomicrotubule-associated proteins and/or totubulin and producesdepolymerization ofmicrotubules (Kd = 10–20 μM for estramustine), resulting in the arrest ofcell division in theG2/M phase (specificallymetaphase).[1][4][42] EMP was originally thought to mediate its cytostatic effects as a prodrug ofnormustine, anitrogen mustard, and hence was thought to be analkylating antineoplastic agent.[3][10][5][14] 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.[1][3][43] As such, the unique properties of the estramustine and estromustinestructures, containing acarbamate-esterbond, appear to be responsible for the cytostatic effects of EMP.[1] In addition to its antimitotic actions, EMP has also been found to produce other cytostatic effects, including induction ofapoptosis, interference withDNA synthesis,nuclear matrix interaction,cell membrane alterations, induction ofreactive oxygen species (free oxygen radicals), and possibly additional mechanisms.[1][4] EMP has been found to have aradiosensitizing effect in prostate cancer andglioma cells, improving sensitivity toradiation therapy as well.[1]
The cytostatic metabolites of EMP are accumulated intissues in aselective manner, for instance inprostate cancercells.[5][1][4] 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, andbreast cancer cells.[1][4][44] 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.[5][4][1]
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 estrogenmoiety for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positivetumor cells.[4][14][2] 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 improvedefficacy andtolerability.[4] However, subsequent research found that there is very limited and slowcleavage of the normustine ester and that EMP is devoid of alkylating activity.[4][1][3][31] 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.[1][3]
Extremely high,pregnancy-like levels of estradiol may be responsible for theleukocytosis (increasedwhite blood cell count) that is observed in individuals treated with EMP.[32][33] This side effect is in contrast to most other cytotoxic agents, which instead causemyelosuppression (bone marrow suppression),leukopenia (decreased white blood cell count), andneutropenia (decreasedneutrophil count).[citation needed]
EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into thecastrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days.[3] Similarly, a dosage of 70 mg/day EMP suppressed testosterone levels into the castrate range within 4 weeks.[3]
| Parameter | IV 300 mg | Oral 420 mg |
|---|---|---|
| Cmax | 506 ± 61 ng/mL | 362 ± 38 ng/mL |
| Tmax | 2.6 ± 0.4 hours | 2.2 ± 0.2 hours |
| t1/2 | 10.3 ± 0.95 hours | 13.6 ± 3.09 hours |
| AUC0–32 | 4.82 ± 0.62 | 2.88 ± 0.34 |
| Bioavailability | 100.0% | 43.7% ± 4.6% |
| Sources:[31] | ||
| Metabolite | Plasma | Ratio |
|---|---|---|
| Estramustine | 20,000–23,000 pg/mL | 1:9.6–9.8 |
| Estromustine | 191,000–267,000 pg/mL | |
| Estradiol | 4,900–9,000 pg/mL | 1:9.4–11.8 |
| Estrone | 71,000–85,000 pg/mL | |
| Sources:[31] | ||
Uponoral ingestion, EMP is rapidly and completelydephosphorylated byphosphatases intoestramustine during thefirst pass in thegastrointestinal tract.[1][4][5][45] Estramustine is also partially but considerablyoxidized intoestromustine by17β-hydroxysteroid dehydrogenases during the first pass.[5][1][12][46] As such, EMP reaches thecirculation as estramustine and estromustine, and the majormetabolite of EMP is estromustine.[1][12] A limited quantity of approximately 10 to 15% of estramustine and estromustine is further slowlymetabolized viahydrolysis of thenormustineester intoestradiol andestrone, respectively.[1][4][31] Thisreaction is believed to becatalyzed bycarbamidases, although thegenes encoding the responsible enzymes have not been characterized.[1][47][48] The circulating levels of normustine formed from EMP are insignificant.[43][49] Release ofnitrogen mustardgas from normustine via cleavage of thecarboxylic acidgroup has not been demonstrated and does not seem to occur.[42][31]
The oralbioavailability of EMP is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of EMP.[1] The oral bioavailability of EMP specifically as estramustine and estromustine is 44 to 75%, suggesting thatabsorption may be incomplete.[1] In any case, there is a linear relationship between the oral dose of EMP and circulating levels of estramustine and estromustine.[1] Consumption ofcalcium,aluminium, ormagnesium with oral EMP can markedly impair its bioavailability due to diminishedabsorption from the intestines, and this may interfere with its therapeutic effectiveness at low doses.[3][17]
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.[1] Estradiol levels with 280 mg/day oral EMP have been found to increase to very high concentrations within one week of therapy.[3] 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.[3] Another study found lower estradiol levels of 4,900 to 9,000 pg/mL during chronic therapy with 560 mg/day oral EMP.[31] 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] 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.[4][31] 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.[1][31] Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-latepregnancy, which range from 5,000 to 40,000 pg/mL.[50] No unchanged EMP is seen in the circulation with oral administration.[1]
Thepharmacokinetics of EMP are different withintravenous injection.[1] Following a single intravenous injection of 300 mg EMP, levels of EMP were higher than those of its metabolites for the first 8 hours.[1] This is likely due to the bypassing of first-pass metabolism.[1] However, by 24 hours after the dose, unchanged EMP could no longer be detected in the circulation.[1] Theclearance of EMP fromblood plasma is 4.85 ± 0.684 L/h.[1] Thevolumes 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.[1] Theplasma protein binding of EMP is high.[1] Estramustine is accumulated intumor tissue, for instanceprostate cancer andglioma tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively).[1] Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively).[1] Estramustine and estromustine appear to accumulate inadipose tissue.[1]
Theelimination half-life of estromustine with oral EMP was 13.6 hours on average, with a range of 8.8 to 22.7 hours.[1] Conversely, the elimination half-life of estromustine with intravenous injection was 10.3 hours, with a range of 7.36 to 12.3 hours.[1] For comparison, the corresponding elimination half-lives of estrone were 16.5 and 14.7 hours for oral and intravenous administration, respectively.[1] Estramustine and estromustine are mainlyexcreted inbile and hence infeces.[1][31] They are not believed to be excreted inurine.[1]
EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is asyntheticestranesteroid and aderivative ofestradiol.[35][15] It is anestrogen ester; specifically, EMP is adiester of estradiol with a C3normustine (nitrogen mustard–carbamatemoiety) ester and a C17βphosphate ester.[35][15] EMP is provided as thesodium ormegluminesalt.[35][15][24] EMP is similar as a compound to otherestradiol esters such asestradiol sulfate andestradiol valerate, but differs in the presence of its nitrogen mustard ester moiety.[35][15]Antineoplastic agents related to EMP, although none of them were marketed, includealestramustine,atrimustine,cytestrol acetate,estradiol mustard,ICI-85966, andphenestrol.[35][15]
Due to itshydrophilic phosphate ester moiety, EMP is a readilywater-soluble compound.[51][52][53] This is in contrast to most other estradiol esters, which arefatty acid esters andlipophilic compounds that are not particularlysoluble inwater.[2] Unlike EMP, estramustine is highly lipophilic, practically insoluble in water, and non-ionizable.[19] The phosphate ester of EMP was incorporated into the molecule in order to increase its water solubility and allow forintravenous administration.[7]
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.[54] 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.[54]
| Estrogen | Structure | Ester(s) | Relative mol. weight | Relative E2 contentb | log Pc | ||||
|---|---|---|---|---|---|---|---|---|---|
| Position(s) | Moiet(ies) | Type | Lengtha | ||||||
| Estradiol | | – | – | – | – | 1.00 | 1.00 | 4.0 | |
| Estradiol acetate |  | C3 | Ethanoic acid | Straight-chain fatty acid | 2 | 1.15 | 0.87 | 4.2 | |
| Estradiol benzoate |  | C3 | Benzoic acid | Aromatic fatty acid | – (~4–5) | 1.38 | 0.72 | 4.7 | |
| Estradiol dipropionate |  | C3, C17β | Propanoic acid (×2) | Straight-chain fatty acid | 3 (×2) | 1.41 | 0.71 | 4.9 | |
| Estradiol valerate |  | C17β | Pentanoic acid | Straight-chain fatty acid | 5 | 1.31 | 0.76 | 5.6–6.3 | |
| Estradiol benzoate butyrate |  | C3, C17β | Benzoic acid,butyric acid | Mixed fatty acid | – (~6, 2) | 1.64 | 0.61 | 6.3 | |
| Estradiol cypionate |  | C17β | Cyclopentylpropanoic acid | Cyclic fatty acid | – (~6) | 1.46 | 0.69 | 6.9 | |
| Estradiol enanthate |  | C17β | Heptanoic acid | Straight-chain fatty acid | 7 | 1.41 | 0.71 | 6.7–7.3 | |
| Estradiol dienanthate |  | C3, C17β | Heptanoic acid (×2) | Straight-chain fatty acid | 7 (×2) | 1.82 | 0.55 | 8.1–10.4 | |
| Estradiol undecylate |  | C17β | Undecanoic acid | Straight-chain fatty acid | 11 | 1.62 | 0.62 | 9.2–9.8 | |
| Estradiol stearate |  | C17β | Octadecanoic acid | Straight-chain fatty acid | 18 | 1.98 | 0.51 | 12.2–12.4 | |
| Estradiol distearate |  | C3, C17β | Octadecanoic acid (×2) | Straight-chain fatty acid | 18 (×2) | 2.96 | 0.34 | 20.2 | |
| Estradiol sulfate |  | C3 | Sulfuric acid | Water-soluble conjugate | – | 1.29 | 0.77 | 0.3–3.8 | |
| Estradiol glucuronide | | C17β | Glucuronic acid | Water-soluble conjugate | – | 1.65 | 0.61 | 2.1–2.7 | |
| Estramustine phosphated | | C3, C17β | Normustine,phosphoric acid | Water-soluble conjugate | – | 1.91 | 0.52 | 2.9–5.0 | |
| Polyestradiol phosphatee |  | C3–C17β | Phosphoric acid | Water-soluble conjugate | – | 1.23f | 0.81f | 2.9g | |
| Footnotes:a = Length ofester incarbonatoms forstraight-chain fatty acids or approximate length of ester in carbon atoms foraromatic orcyclic fatty acids.b = Relative estradiol content by weight (i.e., relativeestrogenic exposure).c = Experimental or predictedoctanol/water partition coefficient (i.e.,lipophilicity/hydrophobicity). Retrieved fromPubChem,ChemSpider, andDrugBank.d = Also known asestradiol normustine phosphate.e =Polymer ofestradiol phosphate (~13repeat units).f = Relative molecular weight or estradiol content per repeat unit.g = log P of repeat unit (i.e., estradiol phosphate).Sources: See individual articles. | |||||||||
EMP was firstsynthesized in the mid-1960s and waspatented in 1967.[42] It was initially developed for the treatment ofbreast cancer.[1] The idea for EMP was inspired by the uptake and accumulation ofradiolabeled estrogens into breast cancer tissue.[1] However, initial clinical findings of EMP in women with breast cancer were disappointing.[1] Subsequently, radiolabeled EMP was found to be taken up into and accumulated ratprostate gland, and this finding culminated in the medication being repurposed for the treatment ofprostate cancer.[1][3] EMP was introduced for medical use in the treatment of this condition in the early 1970s, and was approved in theUnited States for this indication in 1981.[1][3][55] EMP was originally introduced for use by intravenous injection.[31] Subsequently, an oral formulation was introduced, and the intravenous preparation was almost abandoned in favor of the oral version.[31]
EMP is provided as thesodiumsalt fororal administration, which has thegeneric namesestramustine phosphate sodium (USANTooltip United States Adopted Name) andestramustine sodium phosphate (BANMTooltip British Approved Name,JANTooltip Japanese Accepted Name), and as themeglumine salt forintravenous administration, which has the generic nameestramustine phosphate meglumine.[24][35][15][56][16] TheINNMTooltip International Nonproprietary Name isestramustine phosphate.[35] The nameestramustine phosphate is a contraction ofestradiol normustine phosphate.[35][16] EMP is also known by its former developmental code namesLeo 299,Ro 21-8837, andRo 21-8837/001.[35][15][16]
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.[15][16][24]
EMP is marketed in theUnited States,[57]Canada, andMexico under the brand name Emcyt, whereas the medication is marketed under the brand name Estracyt in theUnited Kingdom and elsewhere throughoutEurope as well as inArgentina,Chile, andHong Kong.[15] It has been discontinued in a number of countries, includingAustralia,Brazil,Ireland, andNorway.[58]
EMP has been studied in the treatment of othercancers such asglioma andbreast cancer.[1] It has been found to slightly improvequality of life in people with glioma during the first 3 months of therapy.[1]