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US FDA approved, and the intramuscular injection form of formestane (Lentaron) which was approved in Europe has been withdrawn.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

Similar Structures

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

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.

Formestane
4-Hydroxyandrostenedione glucuronide

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

Clinical Trials: Not Available

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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Details1. Cytochrome P450 3A4

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 April 10, 2019 13:51

Formestane

Identification

Structure for Formestane (DB08905)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Enzymes

References