Toremifene

Identification

Summary

Toremifene is a first generation nonsteroidal selective estrogen receptor modulator used to treat certain breast cancers.

Brand Names
Fareston
Generic Name
Toremifene
DrugBank Accession Number
DB00539
Background

Toremifene is a selective estrogen receptor modulator (SERM) and a nonsteroidal antiestrogen used to treat estrogen receptor positive breast cancer.6 Like tamoxifen, toremifene is part of the first-generation triphenylethylene derivative chemical class of SERMs.7

Toremifene possesses tissue-specific actions: it has estrogenic (agonist) activity on the cardiovascular system and on bone tissue and it has weak estrogenic effects on uterine tissue, however, it also has antiestrogenic (estrogen-antagonist) activity on breast tissue.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 405.96
Monoisotopic: 405.18594223
Chemical Formula
C26H28ClNO
Synonyms
  • Toremifene
  • Toremifeno
  • Toremifenum
External IDs
  • GTX-006
  • J33.157K

Pharmacology

Indication

For 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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofMetastatic breast cancer••••••••••••••••••••••••••
Treatment ofMetastatic breast cancer••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Toremifene 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 action

Toremifene 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.

TargetActionsOrganism
AEstrogen receptor alpha
modulator
Humans
USex hormone-binding globulinNot AvailableHumans
Absorption

Well absorbed

Volume of distribution
  • 580 L
Protein binding

Toremifen 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.

Hover over products below to view reaction partners

Route of elimination

Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency.

Half-life

5 days

Clearance
  • 5 L/h
Adverse Effects
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Toxicity

Not Available

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 Toremifene can be increased when it is combined with Abametapir.
AbciximabThe risk or severity of bleeding can be increased when Toremifene is combined with Abciximab.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Toremifene.
AbrocitinibThe serum concentration of Toremifene can be increased when it is combined with Abrocitinib.
AcenocoumarolThe risk or severity of bleeding can be increased when Toremifene is combined with Acenocoumarol.
Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 and therefore, may elevate toremifene serum levels.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Toremifene citrate2498Y783QT89778-27-8IWEQQRMGNVVKQW-OQKDUQJOSA-N
International/Other Brands
Acapodene
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FarestonTablet60 mg/1OralG Tx1997-06-302016-04-30US flag
FarestonTablet60 mgOralOrion Corporation2016-09-08Not applicableEU flag
FarestonTablet60 mg/1OralKyowa Kirin, Inc.1997-06-30Not applicableUS flag
FarestonTablet60 mgOralOrion Corporation2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Toremifene CitrateTablet60 mg/1OralRising Pharmaceuticals, Inc.2019-01-18Not applicableUS flag
Toremifene CitrateTablet60 mg/1OralNovadoz Pharmaceuticals Llc2020-09-02Not applicableUS flag
Toremifene CitrateTablet60 mg/1OralMsn Laboratories Private Limited2020-08-20Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
FLOBACT - DToremifene (3.5 mg) + Dexamethasone (1.152 mg)SuspensionConjunctival; OphthalmicARBOFARMA S.A.S.2006-11-10Not applicableColombia flag

Categories

ATC Codes
L02BA02 — Toremifene
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Stilbenes
Sub Class
Not Available
Direct Parent
Stilbenes
Alternative Parents
Diphenylmethanes / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Trialkylamines / Organopnictogen compounds / Organochlorides / Hydrocarbon derivatives / Alkyl chlorides
Substituents
Alkyl aryl ether / Alkyl chloride / Alkyl halide / Amine / Aromatic homomonocyclic compound / Benzenoid / Diphenylmethane / Ether / Hydrocarbon derivative / Monocyclic benzene moiety
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
aromatic ether, tertiary amine, organochlorine compound (CHEBI:9635)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7NFE54O27T
CAS number
89778-26-7
InChI Key
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

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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  6. Authors unspecified: Toremifene. . [Article]
  7. Maximov PY, Lee TM, Jordan VC: The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol. 2013 May;8(2):135-55. doi: 10.2174/1574884711308020006. [Article]
Human Metabolome Database
HMDB0014679
KEGG Compound
C08166
PubChem Compound
3005573
PubChem Substance
46506087
ChemSpider
2275722
BindingDB
58492
RxNav
38409
ChEBI
9635
ChEMBL
CHEMBL1655
ZINC
ZINC000012404516
Therapeutic Targets Database
DAP000793
PharmGKB
PA451731
PDBe Ligand
T0R
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Toremifene
PDB Entries
5jq7

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentBreast Cancer1
4Unknown StatusTreatmentFemale Breast Cancer1
4WithdrawnTreatmentHER2 negative / Invasive Breast Carcinoma / Postmenopausal / Stage 0 Breast Cancer / Stage IA Breast Cancer1
3CompletedDiagnosticCirculatory; Change1
3CompletedPreventionBone Fractures / Osteoporosis / Prostate Cancer1

Pharmacoeconomics

Manufacturers
  • Gtx inc
Packagers
  • GTx Inc.
Dosage Forms
FormRouteStrength
TabletOral60 MG
TabletOral60 mg/1
SuspensionConjunctival; Ophthalmic
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)Region
US4696949No1987-09-292009-09-29US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)108-110 °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 FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0a4i-9123000000-e8ca7915f080abef6c64
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0010900000-f55f03796d8b627e24e1
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-2111900000-b83384dedf80b13ebc90
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9010100000-09c5235797bf7614a927
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00dj-9155200000-cb9d94b54bb6d55012bf
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9010000000-c153d9d5d5757f8edd65
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001j-3093000000-24e3a193c98f70cfb72c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-9110000000-b1ef6734e06a3487e295
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-212.4677728
predicted
DarkChem Lite v0.1.0
[M-H]-198.0998
predicted
DeepCCS 1.0 (2019)
[M+H]+212.5383728
predicted
DarkChem Lite v0.1.0
[M+H]+200.4578
predicted
DeepCCS 1.0 (2019)
[M+Na]+212.6286728
predicted
DarkChem Lite v0.1.0
[M+Na]+207.89432
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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 tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
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. [Article]
  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. [Article]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  4. Jones KL, Buzdar AU: A review of adjuvant hormonal therapy in breast cancer. Endocr Relat Cancer. 2004 Sep;11(3):391-406. [Article]
  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. [Article]
  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. [Article]
  7. Lewis-Wambi JS, Jordan VC: Treatment of Postmenopausal Breast Cancer with Selective Estrogen Receptor Modulators (SERMs). Breast Dis. 2005-2006;24:93-105. [Article]
  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. [Article]
  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. [Article]
  10. Goldstein LJ: Controversies in adjuvant endocrine treatment of premenopausal women. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S36-40. [Article]
  11. Smith MR: Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6315s-6319s. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Androgen binding
Specific Function
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone...
Gene Name
SHBG
Uniprot ID
P04278
Uniprot Name
Sex hormone-binding globulin
Molecular Weight
43778.755 Da
References
  1. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W: Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and alpha-fetoprotein. Toxicol Sci. 2015 Feb;143(2):333-48. doi: 10.1093/toxsci/kfu231. Epub 2014 Oct 27. [Article]

Enzymes

Kind
Protein
Organism
Humans
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 un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Berthou F, Dreano Y, Belloc C, Kangas L, Gautier JC, Beaune P: Involvement of cytochrome P450 3A enzyme family in the major metabolic pathways of toremifene in human liver microsomes. Biochem Pharmacol. 1994 May 18;47(10):1883-95. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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. 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. [Article]
  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. [Article]
  3. Berthou F, Dreano Y, Belloc C, Kangas L, Gautier JC, Beaune P: Involvement of cytochrome P450 3A enzyme family in the major metabolic pathways of toremifene in human liver microsomes. Biochem Pharmacol. 1994 May 18;47(10):1883-95. [Article]
  4. Kim J, Peraire C, Sola J, Johanning KM, Dalton JT, Veverka KA: Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms. Xenobiotica. 2011 Oct;41(10):851-62. doi: 10.3109/00498254.2011.590546. Epub 2011 Jul 5. [Article]

Transporters

Kind
Protein
Organism
Humans
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
Uniprot Name
Multidrug resistance protein 1
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. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 03, 2024 02:27