You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameEstramustine
Accession NumberDB01196  (APRD00625)
TypeSmall Molecule
GroupsApproved
Description

A nitrogen mustard linked to estradiol, usually as phosphate; used to treat prostatic neoplasms; also has radiation protective properties. [PubChem]

Structure
Thumb
Synonyms
17beta-Estradiol 3-(bis(2-chloroethyl)carbamate)
17β-Estradiol 3-(bis(2-chloroethyl)carbamate)
Estradiol 3-(N,N-bis(2-chloroethyl)carbamate)
Estramustina
Estramustine
Estramustinum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Emcytcapsule140 mg/1oralPharmacia and Upjohn Company1992-01-01Not applicableUs
Emcytcapsule140 mgoralPfizer Canada Inc1995-12-31Not applicableCanada
Emcyt Cap 140mgcapsule140 mgoralKabi Pharmacia Canada Inc.1993-12-311996-09-10Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
EstracitNot Available
EstracytPfizer
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Estramustin sodium phosphate
Thumb
  • InChI Key: FRPJXPJMRWBBIH-UHFFFAOYNA-N
  • Monoisotopic Mass: 439.168099277
  • Average Mass: 440.403
DBSALT000845
Categories
UNII35LT29625A
CAS number2998-57-4
WeightAverage: 440.403
Monoisotopic: 439.168099277
Chemical FormulaC23H31Cl2NO3
InChI KeyInChIKey=FRPJXPJMRWBBIH-RBRWEJTLSA-N
InChI
InChI=1S/C23H31Cl2NO3/c1-23-9-8-18-17-5-3-16(29-22(28)26(12-10-24)13-11-25)14-15(17)2-4-19(18)20(23)6-7-21(23)27/h3,5,14,18-21,27H,2,4,6-13H2,1H3/t18-,19-,20+,21+,23+/m1/s1
IUPAC Name
(1S,10R,11S,14S,15S)-14-hydroxy-15-methyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-2,4,6-trien-5-yl N,N-bis(2-chloroethyl)carbamate
SMILES
[H][C@@]12CC[[email protected]](O)[C@@]1(C)CC[C@]1([H])C3=CC=C(OC(=O)N(CCCl)CCCl)C=C3CC[C@@]21[H]
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as estrane steroids. These are steroids with a structure based on the estrane skeleton.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassEstrane steroids
Direct ParentEstrane steroids
Alternative Parents
Substituents
  • 17-hydroxysteroid
  • Hydroxysteroid
  • Estrane-skeleton
  • Phenanthrene
  • Tetralin
  • Nitrogen mustard
  • Benzenoid
  • Cyclic alcohol
  • Tertiary amine
  • Secondary alcohol
  • Monocarboxylic acid or derivatives
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl chloride
  • Alcohol
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate
PharmacodynamicsEstramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nitrogen mustard. In vivo, the nitrogen-mustard moiety becomes active and participates in alkylation of DNA or other cellular components.. This causes DNA damage in rapidly dividing cancerous cells leading to cell death and ideally, tumor shrinkage.
Mechanism of actionEstramustine is a derivative of estradiol with a nitrogen mustard moiety. This gives it alkylating properties. In vivo, the nitrogen mustard component is active and can alklyate DNA and other cellular components (such as tubulin components) of rapidly dividing cells. This causes DNA strandbreaks or misscoding events. This leads to apoptosis and cell death. Also, due to the drugs estrogen component, it can bind more selectively to active estrogen receptors.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationThe metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate.
Half life20 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9675
Caco-2 permeable+0.6013
P-glycoprotein substrateSubstrate0.7382
P-glycoprotein inhibitor IInhibitor0.5927
P-glycoprotein inhibitor IINon-inhibitor0.6317
Renal organic cation transporterNon-inhibitor0.5918
CYP450 2C9 substrateNon-substrate0.6261
CYP450 2D6 substrateNon-substrate0.6491
CYP450 3A4 substrateSubstrate0.8003
CYP450 1A2 substrateNon-inhibitor0.6214
CYP450 2C9 inhibitorNon-inhibitor0.6944
CYP450 2D6 inhibitorNon-inhibitor0.6079
CYP450 2C19 inhibitorInhibitor0.5464
CYP450 3A4 inhibitorInhibitor0.8479
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.62
Ames testNon AMES toxic0.6062
CarcinogenicityNon-carcinogens0.8508
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7844 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8235
hERG inhibition (predictor II)Non-inhibitor0.6818
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral140 mg/1
Capsuleoral140 mg
Prices
Unit descriptionCostUnit
Emcyt 140 mg capsule6.55USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point155Fex, H.J., Hogtierg, K.B., Konyves, I. and Kneip, P.H.0.L; U.S. Patent 3,299,104; Jan. 17, 1967; assigned to Leo AB, Sweden.
logP5.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000385 mg/mLALOGPS
logP4.97ALOGPS
logP5.1ChemAxon
logS-6.1ALOGPS
pKa (Strongest Acidic)19.38ChemAxon
pKa (Strongest Basic)-0.88ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area49.77 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity116.21 m3·mol-1ChemAxon
Polarizability48.06 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Fex, H.J., Hogtierg, K.B., Konyves, I. and Kneip, P.H.0.L; U.S. Patent 3,299,104; Jan. 17,
1967; assigned to Leo AB, Sweden.

US3299104
General ReferencesNot Available
External Links
ATC CodesL01XX11
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
Calcium AcetateCalcium Acetate can cause a decrease in the absorption of Estramustine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium carbonateCalcium carbonate can cause a decrease in the absorption of Estramustine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium citrateCalcium citrate can cause a decrease in the absorption of Estramustine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium gluconateCalcium gluconate can cause a decrease in the absorption of Estramustine resulting in a reduced serum concentration and potentially a decrease in efficacy.
ClodronateThe serum concentration of Estramustine can be increased when it is combined with Clodronate.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Estramustine.
LeflunomideThe risk or severity of adverse effects can be increased when Estramustine is combined with Leflunomide.
NatalizumabThe risk or severity of adverse effects can be increased when Estramustine is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Estramustine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Estramustine.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Estramustine.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Estramustine.
TofacitinibEstramustine may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Estramustine.
Food Interactions
  • Do not take with milk or milk products.
  • Take on an empty stomach.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
other/unknown
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by...
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
References
  1. Ho SM: Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. J Cell Biochem. 2004 Feb 15;91(3):491-503. [PubMed:14755680 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription fact...
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
References
  1. Ferno M, Borg A, Ingvar C, Jonsson PE: Estrogen receptor and binding site for estramustine in metastatic malignant melanoma. Anticancer Res. 1987 Jul-Aug;7(4B):741-3. [PubMed:3314674 ]
  2. Yoshizumi N: [The effects of site-directed chemotherapy due to E2 as a drug carrier to the human endometrial adenocarcinoma cells in vitro]. Nihon Sanka Fujinka Gakkai Zasshi. 1985 Apr;37(4):637-45. [PubMed:3989343 ]
  3. von Schoultz E, Carlstrom K, Henriksson R, Lagerlof B, Hansson J: Estramustine binding protein in primary tumours and metastases of malignant melanoma. Melanoma Res. 1994 Dec;4(6):401-5. [PubMed:7703721 ]
  4. Tew KD: The mechanism of action of estramustine. Semin Oncol. 1983 Sep;10(3 Suppl 3):21-6. [PubMed:6364362 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Structural molecule activity
Specific Function:
The exact function of MAP2 is unknown but MAPs may stabilize the microtubules against depolymerization. They also seem to have a stiffening effect on microtubules.
Gene Name:
MAP2
Uniprot ID:
P11137
Molecular Weight:
199524.51 Da
References
  1. Moraga D, Rivas-Berrios A, Farias G, Wallin M, Maccioni RB: Estramustine-phosphate binds to a tubulin binding domain on microtubule-associated proteins MAP-2 and tau. Biochim Biophys Acta. 1992 May 22;1121(1-2):97-103. [PubMed:1599956 ]
  2. Stearns ME, Wang M, Sousa O: Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion. J Cell Sci. 1991 Jan;98 ( Pt 1):55-63. [PubMed:1647395 ]
  3. Friden B, Rutberg M, Deinum J, Wallin M: The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Biochem Pharmacol. 1991 Aug 8;42(5):997-1006. [PubMed:1908244 ]
  4. Burns RG: Stoichiometry of estramustine phosphate binding to MAP2 measured by the disassembly of chick brain MAP2:tubulin microtubules. Cell Motil Cytoskeleton. 1990;17(3):167-73. [PubMed:2125244 ]
  5. Falconer MM, Vielkind U, Brown DL: Association of acetylated microtubules, vimentin intermediate filaments, and MAP 2 during early neural differentiation in EC cell culture. Biochem Cell Biol. 1989 Sep;67(9):537-44. [PubMed:2679799 ]
  6. Tew KD: The mechanism of action of estramustine. Semin Oncol. 1983 Sep;10(3 Suppl 3):21-6. [PubMed:6364362 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Structural molecule activity
Specific Function:
Structural protein involved in the filamentous cross-bridging between microtubules and other skeletal elements.
Gene Name:
MAP1A
Uniprot ID:
P78559
Molecular Weight:
305482.26 Da
References
  1. Stearns ME, Wang M, Sousa O: Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion. J Cell Sci. 1991 Jan;98 ( Pt 1):55-63. [PubMed:1647395 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Yang CP, Shen HJ, Horwitz SB: Modulation of the function of P-glycoprotein by estramustine. J Natl Cancer Inst. 1994 May 4;86(9):723-5. [PubMed:7908991 ]
  2. Tiersten AD, Nelsen C, Talbot S, Vahdat L, Fine R, Troxel A, Brafman L, Shriberg L, Antman K, Petrylak DP: A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma. Cancer. 2003 Feb 1;97(3):537-44. [PubMed:12548594 ]
  3. Smith CD, Zilfou JT, Zhang X, Hudes GR, Tew KD: Modulation of P-glycoprotein activity by estramustine is limited by binding to plasma proteins. Cancer. 1995 May 15;75(10):2597-604. [PubMed:7736407 ]
  4. Speicher LA, Barone LR, Chapman AE, Hudes GR, Laing N, Smith CD, Tew KD: P-glycoprotein binding and modulation of the multidrug-resistant phenotype by estramustine. J Natl Cancer Inst. 1994 May 4;86(9):688-94. [PubMed:7908988 ]
Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23