Identification

Name
Toremifene
Accession Number
DB00539
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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
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.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More
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
Learn about our commercial Adverse Effects data.
Learn More
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 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.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Toremifene.
AcenocoumarolThe risk or severity of bleeding can be increased when Toremifene is combined with Acenocoumarol.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Toremifene is combined with Acetylsalicylic acid.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Toremifene.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Toremifene.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Toremifene.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Toremifene.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Toremifene.
Additional Data Available
  • Extended Description
    Extended Description

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

    Learn more
  • Severity
    Severity

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

    Learn more
  • Evidence Level
    Evidence Level

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

    Learn more
  • Action
    Action

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

    Learn more
Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 and therefore, may elevate toremifene serum levels.
  • Take with or without food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Toremifene citrate2498Y783QT89778-27-8IWEQQRMGNVVKQW-OQKDUQJOSA-N
International/Other Brands
Acapodene
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FarestonTablet60 mg/1OralKYOWA KIRIN, INC,1997-06-30Not applicableUS flag
FarestonTablet60 mgOralOrion Corporation1996-02-14Not applicableEU flag
FarestonTablet60 mg/1OralG Tx1997-06-302016-04-30US flag
FarestonTablet60 mgOralOrion Corporation1996-02-14Not applicableEU 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.

    Learn more
  • Product Code
    Product Code

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

    Learn more
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
Additional Data Available
  • Application Number
    Application Number

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

    Learn more
  • Product Code
    Product Code

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

    Learn more

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)

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. [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]
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
4RecruitingTreatmentFemale Breast Cancer1
4WithdrawnTreatmentHER2/Neu Negative / Invasive Breast Carcinoma / One to five years postmenopausal / Stage 0 Breast Cancer / Stage IA Breast Cancer1
3CompletedDiagnosticCirculatory; Change1
3CompletedPreventionFracture Bone / Osteoporosis / Prostate Cancer1
3CompletedPreventionPreneoplastic Conditions / Prostatic Intraepithelial Neoplasia1
3CompletedTreatmentBreast Cancer1
3CompletedTreatmentBreast Pain1
3CompletedTreatmentNeoplasms, Breast / Neoplasms, Hormone-Dependent1
3Not Yet RecruitingTreatmentBreast Cancer / Chemotherapy Induced Amenorrhea / Ovarian Function Suppression1

Pharmacoeconomics

Manufacturers
  • Gtx inc
Packagers
  • GTx Inc.
Dosage Forms
FormRouteStrength
TabletOral60 mg/1
TabletOral60 mg
SuspensionConjunctival; Ophthalmic3.5 mg
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
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

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-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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0010900000-f55f03796d8b627e24e1

Targets

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. [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]
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. [PubMed:25349334]

Enzymes

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. [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. 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. [PubMed:8204106]
  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. [PubMed:21726172]
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. [PubMed:8204106]

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. [PubMed:7914405]

Drug created on June 13, 2005 07:24 / Updated on June 12, 2020 10:51

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Logo pink
Stay in the know!
As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages.
#DrugBankUpdates