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Identification
NameToremifene
Accession NumberDB00539  (APRD00391)
TypeSmall Molecule
GroupsApproved, Investigational
Description

A first generation nonsteroidal selective estrogen receptor modulator (SERM) that is structurally related to tamoxifen. Like tamoxifen, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue. [PubChem]

Structure
Thumb
Synonyms
Toremifeno
Toremifenum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Farestontablet60 mg/1oralG Tx, Inc.1997-06-30Not applicableUs
Farestontablet60 mg/1oralPro Strakan, Inc.1997-06-30Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AcapodeneNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Toremifene citrate
ThumbNot applicableDBSALT001447
Categories
UNII7NFE54O27T
CAS number89778-26-7
WeightAverage: 405.96
Monoisotopic: 405.18594223
Chemical FormulaC26H28ClNO
InChI KeyInChIKey=XFCLJVABOIYOMF-QPLCGJKRSA-N
InChI
InChI=1S/C26H28ClNO/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16H,17-20H2,1-2H3/b26-25-
IUPAC Name
(2-{4-[(1Z)-4-chloro-1,2-diphenylbut-1-en-1-yl]phenoxy}ethyl)dimethylamine
SMILES
CN(C)CCOC1=CC=C(C=C1)C(=C(\CCCl)C1=CC=CC=C1)\C1=CC=CC=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassStilbenes
Sub ClassNot Available
Direct ParentStilbenes
Alternative Parents
Substituents
  • Stilbene
  • Diphenylmethane
  • Phenylpropene
  • Phenol ether
  • Alkyl aryl ether
  • Benzenoid
  • Monocyclic benzene moiety
  • Tertiary aliphatic amine
  • Tertiary amine
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl chloride
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer.
PharmacodynamicsToremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein.
Mechanism of actionToremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors.
Related Articles
AbsorptionWell absorbed
Volume of distribution
  • 580 L
Protein bindingToremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum.
Metabolism

Hepatic. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo.

SubstrateEnzymesProduct
Toremifene
N-desmethyltoremifeneDetails
Route of eliminationToremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency.
Half life5 days
Clearance
  • 5 L/h
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+0.7488
Caco-2 permeable+0.8266
P-glycoprotein substrateSubstrate0.7067
P-glycoprotein inhibitor IInhibitor0.79
P-glycoprotein inhibitor IINon-inhibitor0.5917
Renal organic cation transporterInhibitor0.7552
CYP450 2C9 substrateNon-substrate0.7502
CYP450 2D6 substrateNon-substrate0.759
CYP450 3A4 substrateSubstrate0.7574
CYP450 1A2 substrateInhibitor0.8683
CYP450 2C9 inhibitorNon-inhibitor0.882
CYP450 2D6 inhibitorInhibitor0.7217
CYP450 2C19 inhibitorNon-inhibitor0.7443
CYP450 3A4 inhibitorNon-inhibitor0.8824
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5128
Ames testNon AMES toxic0.7545
CarcinogenicityNon-carcinogens0.616
BiodegradationNot ready biodegradable0.9601
Rat acute toxicity2.3467 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.7708
hERG inhibition (predictor II)Inhibitor0.5086
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Gtx inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral60 mg/1
Prices
Unit descriptionCostUnit
Fareston 60 mg tablet11.84USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4696949 No1992-09-292009-09-29Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point108-110 °CNot Available
logP6.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000409 mg/mLALOGPS
logP5.65ALOGPS
logP6.27ChemAxon
logS-6ALOGPS
pKa (Strongest Basic)8.76ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity133.41 m3·mol-1ChemAxon
Polarizability46.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Reijo Toivola, Tuomas Huuhtanen, “Toremifene crystallization method.” U.S. Patent US20070093556, issued April 26, 2007.

US20070093556
General References
  1. Price N, Sartor O, Hutson T, Mariani S: Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer. 2005 Mar;3(4):211-4. [PubMed:15882476 ]
  2. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA: Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy. Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. [PubMed:16503765 ]
  3. Thompson IM: Chemoprevention of prostate cancer: agents and study designs. J Urol. 2007 Sep;178(3 Pt 2):S9-S13. Epub 2007 Jul 20. [PubMed:17644117 ]
  4. Ariazi EA, Ariazi JL, Cordera F, Jordan VC: Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6(3):181-202. [PubMed:16515478 ]
  5. Musa MA, Khan MO, Cooperwood JS: Medicinal chemistry and emerging strategies applied to the development of selective estrogen receptor modulators (SERMs). Curr Med Chem. 2007;14(11):1249-61. [PubMed:17504144 ]
External Links
ATC CodesL02BA02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AcenocoumarolToremifene may increase the anticoagulant activities of Acenocoumarol.
AtazanavirThe risk or severity of adverse effects can be increased when Atazanavir is combined with Toremifene.
BexaroteneThe serum concentration of Toremifene can be decreased when it is combined with Bexarotene.
BoceprevirThe risk or severity of adverse effects can be increased when Boceprevir is combined with Toremifene.
BosentanThe serum concentration of Toremifene can be decreased when it is combined with Bosentan.
CarbamazepineThe serum concentration of Toremifene can be decreased when it is combined with Carbamazepine.
CeritinibThe risk or severity of adverse effects can be increased when Ceritinib is combined with Toremifene.
ChlorothiazideChlorothiazide may increase the hypercalcemic activities of Toremifene.
ChlorthalidoneChlorthalidone may increase the hypercalcemic activities of Toremifene.
CitalopramCitalopram may increase the QTc-prolonging activities of Toremifene.
ClarithromycinThe risk or severity of adverse effects can be increased when Clarithromycin is combined with Toremifene.
CobicistatThe risk or severity of adverse effects can be increased when Cobicistat is combined with Toremifene.
DabrafenibThe serum concentration of Toremifene can be decreased when it is combined with Dabrafenib.
DarunavirThe risk or severity of adverse effects can be increased when Darunavir is combined with Toremifene.
DeferasiroxThe serum concentration of Toremifene can be decreased when it is combined with Deferasirox.
DicoumarolToremifene may increase the anticoagulant activities of Dicoumarol.
DofetilideDofetilide may increase the QTc-prolonging activities of Toremifene.
EnzalutamideThe serum concentration of Toremifene can be decreased when it is combined with Enzalutamide.
FosphenytoinThe serum concentration of Toremifene can be decreased when it is combined with Fosphenytoin.
GoserelinGoserelin may increase the QTc-prolonging activities of Toremifene.
HydrochlorothiazideHydrochlorothiazide may increase the hypercalcemic activities of Toremifene.
IdelalisibThe risk or severity of adverse effects can be increased when Idelalisib is combined with Toremifene.
IndinavirThe risk or severity of adverse effects can be increased when Indinavir is combined with Toremifene.
ItraconazoleThe risk or severity of adverse effects can be increased when Itraconazole is combined with Toremifene.
IvabradineIvabradine may increase the QTc-prolonging activities of Toremifene.
KetoconazoleThe risk or severity of adverse effects can be increased when Ketoconazole is combined with Toremifene.
LeuprolideLeuprolide may increase the QTc-prolonging activities of Toremifene.
MethyclothiazideMethyclothiazide may increase the hypercalcemic activities of Toremifene.
MetolazoneMetolazone may increase the hypercalcemic activities of Toremifene.
MifepristoneMifepristone may increase the QTc-prolonging activities of Toremifene.
MitotaneThe serum concentration of Toremifene can be decreased when it is combined with Mitotane.
NefazodoneThe risk or severity of adverse effects can be increased when Nefazodone is combined with Toremifene.
NelfinavirThe risk or severity of adverse effects can be increased when Nelfinavir is combined with Toremifene.
OctreotideOctreotide may increase the QTc-prolonging activities of Toremifene.
OspemifeneThe risk or severity of adverse effects can be increased when Toremifene is combined with Ospemifene.
PhenobarbitalThe serum concentration of Toremifene can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Toremifene can be decreased when it is combined with Phenytoin.
PosaconazoleThe risk or severity of adverse effects can be increased when Posaconazole is combined with Toremifene.
PrimidoneThe serum concentration of Toremifene can be decreased when it is combined with Primidone.
RifabutinThe serum concentration of Toremifene can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Toremifene can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Toremifene can be decreased when it is combined with Rifapentine.
RitonavirThe risk or severity of adverse effects can be increased when Ritonavir is combined with Toremifene.
SaquinavirThe risk or severity of adverse effects can be increased when Saquinavir is combined with Toremifene.
SiltuximabThe serum concentration of Toremifene can be decreased when it is combined with Siltuximab.
St. John's WortThe serum concentration of Toremifene can be decreased when it is combined with St. John's Wort.
SugammadexThe therapeutic efficacy of Sugammadex can be decreased when used in combination with Toremifene.
TelaprevirThe risk or severity of adverse effects can be increased when Telaprevir is combined with Toremifene.
TelithromycinThe risk or severity of adverse effects can be increased when Telithromycin is combined with Toremifene.
TocilizumabThe serum concentration of Toremifene can be decreased when it is combined with Tocilizumab.
TrichlormethiazideTrichlormethiazide may increase the hypercalcemic activities of Toremifene.
VoriconazoleThe risk or severity of adverse effects can be increased when Voriconazole is combined with Toremifene.
WarfarinToremifene may increase the anticoagulant activities of Warfarin.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
modulator
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. Locci P, Bellocchio S, Lilli C, Marinucci L, Cagini L, Baroni T, Giustozzi G, Balducci C, Becchetti E: Synthesis and secretion of transforming growth factor-beta1 by human desmoid fibroblast cell line and its modulation by toremifene. J Interferon Cytokine Res. 2001 Nov;21(11):961-70. [PubMed:11747628 ]
  2. Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, Burdette JE, Bolton JL: Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Chem Res Toxicol. 2003 Jul;16(7):832-7. [PubMed:12870885 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  4. Jones KL, Buzdar AU: A review of adjuvant hormonal therapy in breast cancer. Endocr Relat Cancer. 2004 Sep;11(3):391-406. [PubMed:15369444 ]
  5. Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB: Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv. 2008 Mar;63(3):163-81. doi: 10.1097/OGX.0b013e31816400d7. [PubMed:18279543 ]
  6. Gennari L, Merlotti D, Valleggi F, Martini G, Nuti R: Selective estrogen receptor modulators for postmenopausal osteoporosis: current state of development. Drugs Aging. 2007;24(5):361-79. [PubMed:17503894 ]
  7. Lewis-Wambi JS, Jordan VC: Treatment of Postmenopausal Breast Cancer with Selective Estrogen Receptor Modulators (SERMs). Breast Dis. 2005-2006;24:93-105. [PubMed:16917142 ]
  8. Ariazi EA, Ariazi JL, Cordera F, Jordan VC: Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6(3):181-202. [PubMed:16515478 ]
  9. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA: Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy. Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. [PubMed:16503765 ]
  10. Goldstein LJ: Controversies in adjuvant endocrine treatment of premenopausal women. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S36-40. [PubMed:16595024 ]
  11. Smith MR: Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6315s-6319s. [PubMed:17062721 ]

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. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA: Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy. Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. [PubMed:16503765 ]
  2. Kivisto KT, Villikka K, Nyman L, Anttila M, Neuvonen PJ: Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther. 1998 Dec;64(6):648-54. [PubMed:9871429 ]
  3. 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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d 24-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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular Weight:
58164.815 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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 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
substrate
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. Rao US, Fine RL, Scarborough GA: Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92. [PubMed:7914405 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on November 30, 2015 12:10