Identification

Name
Formestane
Accession Number
DB08905
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Formestane was the first selective, type I, steroidal aromatase inhibitor used in the treatment of estrogen-receptor positive breast cancer in post-menopausal women. Formestane suppresses estrogen production from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a mild aromatase inhibitor. It is listed as a prohibited substance by the World Anti-Doping Agency for use in athletes.

Formestane has poor oral bioavailability, and thus must be administered forthnightly (bi-weekly) by intramuscular injection. Some clinical data has suggested that the clinically recommended dose of 250mg was too low. With the discovery of newer, non-steroidal and steroidal, aromatase inhibitors which were orally active and less expensive than formestane, formestane lost popularity.

Currently, formestane (categorized as an anti-estrogenic agent) is prohibited from use in sports in accordance to the regulations of the World Anti-Doping Agency. It is not US FDA approved, and the intramuscular injection form of formestane (Lentaron) which was approved in Europe has been withdrawn.

Structure
Thumb
Synonyms
  • 4-hydroxy-4-androstene-3,17-dione
  • 4-Hydroxy-delta(4)-androstenedione
  • 4-hydroxy-Δ4-androstenedione
  • 4-hydroxyandrostenedione
  • 4-OH-A
  • 4-OHAD
  • Formestano
  • Formestanum
External IDs
CGP 32349 / CGP-32349
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
LentaronFormestane (250 mg) + Sodium Chloride (.9 %)Liquid; Powder, for solutionIntramuscularNovartis1994-12-311999-08-04Canada
International/Other Brands
Lentaron
Categories
UNII
PUB9T8T355
CAS number
566-48-3
Weight
Average: 302.4079
Monoisotopic: 302.188194698
Chemical Formula
C19H26O3
InChI Key
OSVMTWJCGUFAOD-KZQROQTASA-N
InChI
InChI=1S/C19H26O3/c1-18-10-8-15(20)17(22)14(18)4-3-11-12-5-6-16(21)19(12,2)9-7-13(11)18/h11-13,22H,3-10H2,1-2H3/t11-,12-,13-,18+,19-/m0/s1
IUPAC Name
(1S,2R,10R,11S,15S)-6-hydroxy-2,15-dimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadec-6-ene-5,14-dione
SMILES
[H][C@@]12CCC(=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=C(O)C(=O)CC[C@]12C

Pharmacology

Indication

For the treatment of estrogen-receptor positive breast cancer in post-menopausal women.

Pharmacodynamics

By significantly reducing estrogen levels in the bloodstream, formestane may exhibit antitumor activity.

In one trial involving 147 postmenopausal females with advanced breast cancers resistant to standard therapies, 22% of patients achieved a partial response, while another 20% achieved disease stabilization. [3]

In comparative trials comparing a non-steroidal aromatase inhibitor, anastrozole, with formestane, it was found that anastrozole was more effective and consistent at suppressing estrogen levels in the body. However, these results were of unverified clinical significance. [5]

Mechanism of action

Formestane is a second generation, irreversible, steroidal aromatase inhibitor. It inhibits the aromatase enzyme responsible for converting androgens to estrogens, thereby preventing estrogen production.

Breast cancer may be estrogen sensitive or insensitive. A majority of breast cancers are estrogen sensitive. Estrogen sensitive breast cancer cells depend on estrogen for viability. Thus removal of estrogen from the body can be an effective treatment for hormone sensitive breast cancers.

Formestane has been targeted specifically for the treatment of postmenopausal women. Unlike premenopausal women who produce most estrogen in the ovaries, postmenopausal women produce most estrogen in peripheral tissues with the help of the aromatase enzyme. Formestane, an aromatase inhibitor, can thus help to decrease the local production of estrogen by blocking the aromatase enzyme in peripheral tissues (ie. adispose tissue of the breast) to treat hormone sensitive breast cancer.

Absorption

Formestane has poor oral bioavailability, but is fully bioavailable when administered via the established intramuscular route. The AUC after an intravenous pulse dose does not vary considerably from that of an intramuscular dose.

Within 24-48 h of the first dose of intramuscular formestane, a C(max) of 48.0 +/- 20.9 nmol/l was achieved in one study. [2]

Volume of distribution

Vd = 1.8 L/kg; widely distributed to organs and tissues when delivered intravenously. [2]

Protein binding
Not Available
Metabolism

Hepatic metabolism. Phase I of metabolism is mainly reductive in nature. The reduction products 3 beta-hydroxy-5alpha-androstane-4,17-dione and 3alpha-hydroxy-5beta-androstane-4,17-dione are produced, and further reduced. A notable step in the process of metabolism is a keto reduction on carbon number three of the molecule. The main metabolite which is produced from formestane is 4-hydroyxyandrost-4-ene-3,17-dione-4-glucuronide.

The oxidation products identified were 4-hydroxyandrosta-4,6-diene-3,17-dione and 4-hydroxyandrosta-1,4-diene-3,17-dione.

In phase II, conjugation was diverse and included sulfatation and glucuronidation. 4-hydroxytestosterone, the 17-hydroxylated analog to formestane, was identified as one particular metabolite found in women's urine. This finding was the result of an oral administration of 500mg of formestane in women.

Route of elimination

Renal elimination. >95% in urine, <5% in feces.

Half life

Terminal plasma elimination half life of 18 minutes, when delivered intravenously. [2]

Clearance

Plasma clearance is approximately 4.2 L/(h kg), when delivered intravenously.

In women, following a 500mg dose of formestane, 20% was excreted as glucuronide within the first 24 hours. [1]

One long term metabolite (3beta,4alpha-dihydroxy-5alpha-androstan-17-one) can be detected for 90 hours. A longer detection time is possible with more sensitive technology, which may be of utility in sports drug testing. [1]

Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Formestane.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Formestane.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Formestane.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Formestane.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Formestane.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Formestane.
AbacavirAbacavir may decrease the excretion rate of Formestane which could result in a higher serum level.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Formestane.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Formestane.
AcarboseAcarbose may decrease the excretion rate of Formestane which could result in a higher serum level.
Food Interactions
Not Available

References

Synthesis Reference

Kohler, Maxie, et al. "Metabolism of 4-hydroxyandrostenedione and 4-hydroxytestosterone: Mass spectrometric identification of urinary metabolites." Steroids 72.3 (2007): 278-286.

General References
  1. Perez Carrion R, Alberola Candel V, Calabresi F, Michel RT, Santos R, Delozier T, Goss P, Mauriac L, Feuilhade F, Freue M, et al.: Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Ann Oncol. 1994;5 Suppl 7:S19-24. [PubMed:7873457]
  2. Kohler M, Parr MK, Opfermann G, Thevis M, Schlorer N, Marner FJ, Schanzer W: Metabolism of 4-hydroxyandrostenedione and 4-hydroxytestosterone: Mass spectrometric identification of urinary metabolites. Steroids. 2007 Mar;72(3):278-86. Epub 2007 Jan 17. [PubMed:17207827]
  3. Lonning PE, Geisler J, Johannessen DC, Gschwind HP, Waldmeier F, Schneider W, Galli B, Winkler T, Blum W, Kriemler HP, Miller WR, Faigle JW: Pharmacokinetics and metabolism of formestane in breast cancer patients. J Steroid Biochem Mol Biol. 2001 Apr;77(1):39-47. [PubMed:11358673]
  4. Murray R, Pitt P: Treatment of advanced breast cancer with formestane. Ann Oncol. 1994;5 Suppl 7:S11-3. [PubMed:7873455]
  5. Vorobiof DA, Kleeberg UR, Perez-Carrion R, Dodwell DJ, Robertson JF, Calvo L, Dowsett M, Clack G: A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal women with advanced breast cancer. Ann Oncol. 1999 Oct;10(10):1219-25. [PubMed:10586340]
External Links
KEGG Drug
D07260
PubChem Compound
11273
PubChem Substance
175427144
ChemSpider
10799
BindingDB
225704
ChEBI
75172
ChEMBL
CHEMBL132530
Drugs.com
Drugs.com Drug Page
Wikipedia
Formestane
ATC Codes
L02BG02 — Formestane
MSDS
Download (279 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Liquid; powder, for solutionIntramuscular
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)199 - 202 MSDS
water solubilityInsoluble MSDS
logP2.66MSDS
pKa9.31MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0578 mg/mLALOGPS
logP2.57ALOGPS
logP3.41ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)9.21ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area54.37 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity85.57 m3·mol-1ChemAxon
Polarizability34.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9628
Caco-2 permeable+0.8149
P-glycoprotein substrateSubstrate0.6597
P-glycoprotein inhibitor IInhibitor0.7113
P-glycoprotein inhibitor IINon-inhibitor0.8526
Renal organic cation transporterNon-inhibitor0.7227
CYP450 2C9 substrateNon-substrate0.8331
CYP450 2D6 substrateNon-substrate0.9308
CYP450 3A4 substrateSubstrate0.753
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9443
CYP450 2D6 inhibitorNon-inhibitor0.941
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.85
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9027
Ames testNon AMES toxic0.9311
CarcinogenicityNon-carcinogens0.9537
BiodegradationNot ready biodegradable0.963
Rat acute toxicity1.6135 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9479
hERG inhibition (predictor II)Non-inhibitor0.7566
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 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/MSsplash10-01t9-2920000000-24696d73561fe3ce6680

Taxonomy

Description
This compound belongs to the class of organic compounds known as androgens and derivatives. These are 3-hydroxylated C19 steroid hormones. They are known to favor the development of masculine characteristics. They also show profound effects on scalp and body hair in humans.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Androstane steroids
Direct Parent
Androgens and derivatives
Alternative Parents
Hydroxysteroids / 3-oxo delta-4-steroids / 17-oxosteroids / Delta-4-steroids / Cyclohexenones / Enols / Organic oxides / Hydrocarbon derivatives
Substituents
Androgen-skeleton / 3-oxo-delta-4-steroid / 3-oxosteroid / Oxosteroid / 17-oxosteroid / 4-hydroxysteroid / Hydroxysteroid / Delta-4-steroid / Cyclohexenone / Cyclic ketone
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
enol, 3-oxo Delta(4)-steroid, 17-oxo steroid, hydroxy steroid (CHEBI:75172)

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
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. Blog [Link]

Drug created on June 13, 2013 22:20 / Updated on November 02, 2018 06:55