Identification

Name
Estramustine
Accession Number
DB01196
Description

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

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 440.403
Monoisotopic: 439.168099277
Chemical Formula
C23H31Cl2NO3
Synonyms
  • 17β-Estradiol 3-(bis(2-chloroethyl)carbamate)
  • Estradiol 3-(N,N-bis(2-chloroethyl)carbamate)
  • Estramustina
  • Estramustine
  • Estramustinum
External IDs
  • RO 22-2296/000

Pharmacology

Indication

For the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Estramustine 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 action

Estramustine 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.

TargetActionsOrganism
AMicrotubule-associated protein 2
antagonist
Humans
AMicrotubule-associated protein 1A
antagonist
Humans
AEstrogen receptor alpha
agonist
Humans
AEstrogen receptor beta
other/unknown
Humans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

The 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-life

20 hours

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Estramustine can be increased when it is combined with Abametapir.
AbataceptThe risk or severity of adverse effects can be increased when Estramustine is combined with Abatacept.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Estramustine.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Estramustine.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Estramustine.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Estramustine.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Estramustine.
AltretamineThe risk or severity of adverse effects can be increased when Altretamine is combined with Estramustine.
AmsacrineThe risk or severity of adverse effects can be increased when Amsacrine is combined with Estramustine.
AnakinraThe risk or severity of adverse effects can be increased when Anakinra is combined with Estramustine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid milk and dairy products.
  • Take on an empty stomach.

Products

Product Ingredients
IngredientUNIICASInChI Key
Estramustin sodium phosphate75F375MT2N1227300-83-5FRPJXPJMRWBBIH-UHFFFAOYSA-N
International/Other Brands
Estracit / Estracyt (Pfizer)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EmcytCapsule140 mg/1OralPharmacia and Upjohn Company LLC1992-01-01Not applicableUS flag
EmcytCapsule140 mgOralPfizer Canada Ulc1995-12-312020-04-30Canada flag
Emcyt Cap 140mgCapsuleOralKabi Pharmacia Canada Inc.1993-12-311996-09-10Canada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XX11 — Estramustine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as estrane steroids. These are steroids with a structure based on the estrane skeleton.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Estrane steroids
Direct Parent
Estrane steroids
Alternative Parents
17-hydroxysteroids / Phenanthrenes and derivatives / Tetralins / Nitrogen mustard compounds / Carbamate esters / Secondary alcohols / Organic carbonic acids and derivatives / Cyclic alcohols and derivatives / Organopnictogen compounds / Organochlorides
show 4 more
Substituents
17-hydroxysteroid / Alcohol / Alkyl chloride / Alkyl halide / Aromatic homopolycyclic compound / Benzenoid / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Cyclic alcohol
show 15 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
carbamate ester, organochlorine compound, 17beta-hydroxy steroid (CHEBI:4868) / C18 steroids (estrogens) and derivatives, Estrane and derivatives (C11228) / C18 steroids (estrogens) and derivatives (LMST02010038)

Chemical Identifiers

UNII
35LT29625A
CAS number
2998-57-4
InChI Key
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][[email protected]@]12CC[[email protected]](O)[[email protected]@]1(C)CC[[email protected]]1([H])C3=CC=C(OC(=O)N(CCCl)CCCl)C=C3CC[[email protected]@]21[H]

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 References
Not Available
Human Metabolome Database
HMDB0015327
KEGG Drug
D04066
KEGG Compound
C11228
PubChem Compound
259331
PubChem Substance
46508765
ChemSpider
227635
BindingDB
50333646
RxNav
4089
ChEBI
4868
ChEMBL
CHEMBL1575
ZINC
ZINC000004099032
Therapeutic Targets Database
DAP001307
PharmGKB
PA449507
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Estramustine
AHFS Codes
  • 10:00.00 — Antineoplastic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentProstate Cancer1
3CompletedTreatmentProstate Cancer5
3TerminatedTreatmentProstate Cancer1
3TerminatedTreatmentProstatic Neoplasms1
2Active Not RecruitingTreatmentProstate Cancer1
2CompletedTreatmentAdenocarcinoma of the Prostate / Hormone-Resistant Prostate Cancer / Recurrent Prostate Cancer / Stage IV Prostate Cancer1
2CompletedTreatmentAdenocarcinoma of the Prostate / Prostate Cancer1
2CompletedTreatmentAdenocarcinoma, Prostate1
2CompletedTreatmentBreast Cancer1
2CompletedTreatmentHormone Resistant Prostate Cancer / Metastatic Hormone Refractory Prostate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Pfizer Inc.
  • Pharmaceutical Utilization Management Program VA Inc.
  • Pharmacia Inc.
Dosage Forms
FormRouteStrength
CapsuleOral140 mg/1
CapsuleOral
CapsuleOral140 MG
Capsule140 mg
Injection300 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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)155Fex, 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 FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
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
Uniprot Name
Microtubule-associated protein 2
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
Humans
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
Uniprot Name
Microtubule-associated protein 1A
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]
Kind
Protein
Organism
Humans
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 tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
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
Humans
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 m...
Gene Name
ESR2
Uniprot ID
Q92731
Uniprot Name
Estrogen receptor beta
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]

Enzymes

Kind
Protein
Organism
Humans
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kelly WK, Zhu AX, Scher H, Curley T, Fallon M, Slovin S, Schwartz L, Larson S, Tong W, Hartley-Asp B, Pellizzoni C, Rocchetti M: Dose escalation study of intravenous estramustine phosphate in combination with Paclitaxel and Carboplatin in patients with advanced prostate cancer. Clin Cancer Res. 2003 Jun;9(6):2098-107. [PubMed:12796374]

Transporters

Kind
Protein
Organism
Humans
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
Uniprot Name
Multidrug resistance protein 1
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]

Drug created on June 13, 2005 07:24 / Updated on October 21, 2020 01:55

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