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Identification
NameFulvestrant
Accession NumberDB00947  (APRD00654)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Fulvestrant is a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor.

Structure
Thumb
Synonyms
ICI 182,780
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Faslodexinjection50 mg/mLintramuscularAstra Zeneca Pharmaceuticals Lp2010-11-01Not applicableUs
Faslodexsolution50 mgintramuscularAstrazeneca Canada Inc2004-06-14Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII22X328QOC4
CAS number129453-61-8
WeightAverage: 606.771
Monoisotopic: 606.316607085
Chemical FormulaC32H47F5O3S
InChI KeyInChIKey=VWUXBMIQPBEWFH-LQKBAPIOSA-N
InChI
InChI=1S/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29?,30+,41?/m1/s1
IUPAC Name
(1S,9R,11S,14S,15S)-15-methyl-9-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)nonyl]tetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-2,4,6-triene-5,14-diol
SMILES
[H][C@@]12CC[[email protected]](O)[C@@]1(C)CC[C@@]1([H])C2[[email protected]](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=CC(O)=CC=C12
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassEstrane steroids
Direct ParentEstrogens and derivatives
Alternative Parents
Substituents
  • Estrogen-skeleton
  • 17-hydroxysteroid
  • Hydroxysteroid
  • 3-hydroxysteroid
  • Phenanthrene
  • Tetralin
  • Benzenoid
  • Cyclic alcohol
  • Sulfoxide
  • Secondary alcohol
  • Sulfinyl compound
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organofluoride
  • Organohalogen compound
  • Alkyl halide
  • Alkyl fluoride
  • Alcohol
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.
PharmacodynamicsFulvestrant for intramuscular administration is an estrogen receptor antagonist without known agonist effects.
Mechanism of actionFulvestrant competitively and reversibly binds to estrogen receptors present in cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, fulvestrant binds to the receptors and downregulates them so that estrogen is no longer able to bind to these receptors. Second, fulvestrant degrades the estrogen receptors to which it is bound. Both of these mechanisms inhibit the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines.
Related Articles
AbsorptionNot Available
Volume of distribution
  • 3 to 5 L/kg
Protein binding99% (mainly VLDL, LDL, and HDL)
Metabolism

Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.

Route of eliminationFulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).
Half life40 days
ClearanceNot Available
ToxicityThere is no clinical experience with overdosage in humans.
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+0.9217
Caco-2 permeable-0.5095
P-glycoprotein substrateSubstrate0.722
P-glycoprotein inhibitor INon-inhibitor0.6251
P-glycoprotein inhibitor IINon-inhibitor0.967
Renal organic cation transporterNon-inhibitor0.7568
CYP450 2C9 substrateNon-substrate0.7667
CYP450 2D6 substrateNon-substrate0.7737
CYP450 3A4 substrateSubstrate0.6945
CYP450 1A2 substrateNon-inhibitor0.6842
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.658
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6701
Ames testNon AMES toxic0.6318
CarcinogenicityNon-carcinogens0.75
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6310 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6158
hERG inhibition (predictor II)Inhibitor0.7955
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Astrazeneca pharmaceuticals lp
Packagers
Dosage forms
FormRouteStrength
Injectionintramuscular50 mg/mL
Solutionintramuscular50 mg
Prices
Unit descriptionCostUnit
Faslodex 125 mg/2.5 ml syringe240.83USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2351004 No2003-02-182021-01-08Canada
US6774122 Yes2001-07-092021-07-09Us
US7456160 Yes2001-07-092021-07-09Us
US8329680 Yes2001-07-092021-07-09Us
US8466139 Yes2001-07-092021-07-09Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP8.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00672 mg/mLALOGPS
logP6.54ALOGPS
logP7.57ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)10.32ChemAxon
pKa (Strongest Basic)-0.88ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.53 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity155.34 m3·mol-1ChemAxon
Polarizability65.64 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N: Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol. 2005 Jul 15;239(1-2):27-36. [PubMed:15950373 ]
  2. Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. doi: 10.1517/14656561003641982. [PubMed:20151846 ]
  3. Bross PF, Cohen MH, Williams GA, Pazdur R: FDA drug approval summaries: fulvestrant. Oncologist. 2002;7(6):477-80. [PubMed:12490735 ]
External Links
ATC CodesL02BA03
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelDownload (520 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
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. Curran M, Wiseman L: Fulvestrant. Drugs. 2001;61(6):807-13; discussion 814. [PubMed:11398912 ]
  2. Elkak AE, Mokbel K: Pure antiestrogens and breast cancer. Curr Med Res Opin. 2001;17(4):282-9. [PubMed:11922402 ]
  3. Dow KH: Existing and emerging endocrine therapies for breast cancer. Cancer Nurs. 2002 Apr;25 Suppl 2:6S-11S. [PubMed:12080538 ]
  4. Bundred N, Howell A: Fulvestrant (Faslodex): current status in the therapy of breast cancer. Expert Rev Anticancer Ther. 2002 Apr;2(2):151-60. [PubMed:12113237 ]
  5. Morris C, Wakeling A: Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer. 2002 Dec;9(4):267-76. [PubMed:12542403 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. doi: 10.1517/14656561003641982. [PubMed:20151846 ]
  8. McKeage K, Curran MP, Plosker GL: Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Drugs. 2004;64(6):633-48. [PubMed:15018596 ]
  9. Jones SE, Pippen J: Effectiveness and tolerability of fulvestrant in postmenopausal women with hormone receptor-positive breast cancer. Clin Breast Cancer. 2005 Apr;6 Suppl 1:S9-14. [PubMed:15865850 ]

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 ]
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Drug created on June 13, 2005 07:24 / Updated on July 27, 2016 03:12