Formestane
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- Approved, Investigational, Withdrawn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US FDA approved, and the intramuscular injection form of formestane (Lentaron) which was approved in Europe has been withdrawn.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
- Synonyms
- 4-hydroxy-4-androstene-3,17-dione
- 4-Hydroxy-delta(4)-androstenedione
- 4-hydroxy-Δ4-androstenedione
- 4-hydroxyandrostenedione
- 4-OH-A
- 4-OHAD
- Formestane
- Formestano
- Formestanum
- External IDs
- CGP 32349 / CGP-32349
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Lentaron Formestane (250 mg) + Sodium Chloride (.9 %) Liquid; Powder, for solution Intramuscular Novartis 1994-12-31 1999-08-04 Canada - International/Other Brands
- Lentaron
- Categories
- 17-Ketosteroids
- Adrenal Cortex Hormones
- Androstanes
- Androstenes
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Aromatase Inhibitors
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 Enzyme Inducers
- Endocrine Therapy
- Enzyme Inhibitors
- Estrogen Antagonists
- Gonadal Hormones
- Gonadal Steroid Hormones
- Hormone Antagonists
- Hormone Antagonists and Related Agents
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Ketosteroids
- Steroid Synthesis Inhibitors
- Steroids
- Testosterone Congeners
- 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
Drug Interaction (R)-warfarin The metabolism of (R)-warfarin can be increased when combined with Formestane. (S)-Warfarin The metabolism of (S)-Warfarin can be increased when combined with Formestane. 3,5-diiodothyropropionic acid The metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Formestane. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be increased when combined with Formestane. 5-androstenedione The metabolism of 5-androstenedione can be increased when combined with Formestane. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be increased when combined with Formestane. 7-ethyl-10-hydroxycamptothecin The metabolism of 7-ethyl-10-hydroxycamptothecin can be increased when combined with Formestane. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be increased when combined with Formestane. Abacavir Abacavir may decrease the excretion rate of Formestane which could result in a higher serum level. Abemaciclib The metabolism of Abemaciclib can be increased when combined with Formestane. - 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
- 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]
- 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]
- 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]
- Murray R, Pitt P: Treatment of advanced breast cancer with formestane. Ann Oncol. 1994;5 Suppl 7:S11-3. [PubMed:7873455]
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Liquid; powder, for solution Intramuscular - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 199 - 202 MSDS water solubility Insoluble MSDS logP 2.66 MSDS pKa 9.31 MSDS - Predicted Properties
Property Value Source Water Solubility 0.0578 mg/mL ALOGPS logP 2.57 ALOGPS logP 3.41 ChemAxon logS -3.7 ALOGPS pKa (Strongest Acidic) 9.21 ChemAxon pKa (Strongest Basic) -3.7 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 54.37 Å2 ChemAxon Rotatable Bond Count 0 ChemAxon Refractivity 85.57 m3·mol-1 ChemAxon Polarizability 34.07 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9628 Caco-2 permeable + 0.8149 P-glycoprotein substrate Substrate 0.6597 P-glycoprotein inhibitor I Inhibitor 0.7113 P-glycoprotein inhibitor II Non-inhibitor 0.8526 Renal organic cation transporter Non-inhibitor 0.7227 CYP450 2C9 substrate Non-substrate 0.8331 CYP450 2D6 substrate Non-substrate 0.9308 CYP450 3A4 substrate Substrate 0.753 CYP450 1A2 substrate Non-inhibitor 0.9046 CYP450 2C9 inhibitor Non-inhibitor 0.9443 CYP450 2D6 inhibitor Non-inhibitor 0.941 CYP450 2C19 inhibitor Non-inhibitor 0.9025 CYP450 3A4 inhibitor Non-inhibitor 0.85 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9027 Ames test Non AMES toxic 0.9311 Carcinogenicity Non-carcinogens 0.9537 Biodegradation Not ready biodegradable 0.963 Rat acute toxicity 1.6135 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9479 hERG inhibition (predictor II) Non-inhibitor 0.7566
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available MS/MS Spectrum - , positive LC-MS/MS splash10-01t9-2920000000-24696d73561fe3ce6680
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
- Humans
- 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
- Blog [Link]
Drug created on June 13, 2013 22:20 / Updated on December 14, 2018 05:42