DrugBank: Fulvestrant (DB00947)

targets (1) enzymes (1)

Identification

Name

Fulvestrant

Accession Number

DB00947 (APRD00654)

Type

small molecule

Groups

approved

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

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

fulvestrant
ICI 182,780

Brand names

Faslodex

Brand name mixtures

Not Available

Categories

Antineoplastic Agents
Antineoplastic Agents, Hormonal
Estrogen Antagonists

CAS number

129453-61-8

Weight

Average: 606.771
Monoisotopic: 606.316607085

Chemical Formula

C₃₂H₄₇F₅O₃S

InChI Key

InChIKey=VWUXBMIQPBEWFH-WCCTWKNTSA-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

Plain Text

IUPAC Name

(1S,9R,10R,11S,14S,15S)-15-methyl-9-{9-[(4,4,5,5,5-pentafluoropentane)sulfinyl]nonyl}tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-2(7),3,5-triene-5,14-diol

SMILES

[H][C@@]12CC[C@H](O)[C@@]1(C)CC[C@]1([H])C3=C(C[C@@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)[C@@]21[H])C=C(O)C=C3

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Steroids and Steroid Derivatives

Substructures

Steroids and Steroid Derivatives
Hydroxy Compounds
Naphthalenes
Alkyl Halides
Phenols and Derivatives
Benzene and Derivatives
Phenanthrenes
Aromatic compounds
Alcohols and Polyols
Cyclohexenes and Derivatives
Phenyl Esters
Sulfoxides

Pharmacology

Indication

For the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

Pharmacodynamics

Fulvestrant for intramuscular administration is an estrogen receptor antagonist without known agonist effects.

Mechanism of action

Fulvestrant 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.

Absorption

Not Available

Volume of distribution

3 to 5 L/kg

Protein binding

99% (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 elimination

Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).

Half life

40 days

Clearance

Not Available

Toxicity

There is no clinical experience with overdosage in humans.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Astrazeneca pharmaceuticals lp

Packagers

Dosage forms

Form	Route	Strength
Solution	Intramuscular

Prices

Unit description	Cost	Unit
Faslodex 125 mg/2.5 ml syringe	240.83 USD	ml

Patents

Country	Patent Number	Approved	Expires
United States	6774122	2001-01-09	2021-01-09
Canada	2351004	2003-02-18	2021-01-08

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
logP	8.9	PhysProp

Predicted Properties

Property	Value	Source
water solubility	6.72e-03 g/l	ALOGPS
logP	6.54	ALOGPS
logP	7.57	ChemAxon Molconvert
logS	-4.96	ALOGPS
pKa	19.38	ChemAxon Molconvert
hydrogen acceptor count	3	ChemAxon Molconvert
hydrogen donor count	2	ChemAxon Molconvert
polar surface area	57.53	ChemAxon Molconvert
rotatable bond count	15	ChemAxon Molconvert
refractivity	155.34	ChemAxon Molconvert
polarizability	66.06	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

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
Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. Pubmed
Bross PF, Cohen MH, Williams GA, Pazdur R: FDA drug approval summaries: fulvestrant. Oncologist. 2002;7(6):477-80. Pubmed

External Links

Resource	Link
KEGG Drug	D01161
PubChem Compound	104741
PubChem Substance	46508664
ChemSpider	94553
BindingDB	50169743
ChEBI	31638
ChEMBL	31638
Therapeutic Targets Database	DAP000319
PharmGKB	PA10086
Drug Product Database	2248624
RxList	http://www.rxlist.com/cgi/generic/faslodex.htm
Drugs.com	http://www.drugs.com/cdi/fulvestrant.html
Wikipedia	http://en.wikipedia.org/wiki/Fulvestrant

ATC Codes

L02BA03

AHFS Codes

10:00.00

PDB Entries

Not Available

FDA label

show (520 KB)

MSDS

Not Available

Interactions

Drug Interactions

Drug	Interaction

Food Interactions

Not Available

Targets
1. Estrogen receptor Pharmacological action: yes Actions: antagonist 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 Organism class: human UniProt ID: P03372 Gene: ESR1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Curran M, Wiseman L: Fulvestrant. Drugs. 2001;61(6):807-13; discussion 814. Pubmed Elkak AE, Mokbel K: Pure antiestrogens and breast cancer. Curr Med Res Opin. 2001;17(4):282-9. Pubmed Dow KH: Existing and emerging endocrine therapies for breast cancer. Cancer Nurs. 2002 Apr;25 Suppl 2:6S-11S. Pubmed 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 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 Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. Pubmed 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 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

Targets

1. Estrogen receptor

Pharmacological action: yes
Actions: antagonist

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

Organism class: human
UniProt ID: P03372 Link_out

Gene: ESR1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Curran M, Wiseman L: Fulvestrant. Drugs. 2001;61(6):807-13; discussion 814. Pubmed
Elkak AE, Mokbel K: Pure antiestrogens and breast cancer. Curr Med Res Opin. 2001;17(4):282-9. Pubmed
Dow KH: Existing and emerging endocrine therapies for breast cancer. Cancer Nurs. 2002 Apr;25 Suppl 2:6S-11S. Pubmed
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
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
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. Pubmed
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
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

Enzymes
1. Cytochrome P450 3A4 Actions: substrate 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 xenobiotics. The enzyme also hydroxylates etoposide UniProt ID: P08684 Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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. Epub 2009 Nov 24. Pubmed

Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out

Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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. Epub 2009 Nov 24. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:07

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.