Formestane, formerly sold under the brand name Lentaron among others, is a steroidal, selective aromatase inhibitor which is used in the treatment of estrogen receptor-positive breast cancer in postmenopausal women. The drug is not active orally, and was available only as an intramuscular depot injection. Formestane was not approved by the United States FDA and the injectable form that was used in Europe in the past has been withdrawn from the market. Formestane is an analogue of androstenedione.
Formestane is often used to suppress the production of estrogens 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 weak aromatase inhibitor.
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Suprabhat Ray, Indra Dwivedy, in Advances in Drug Research, 1997
220.127.116.11 4-Substituted ADD Derivatives
Formestane (4-hydroxy-androst-4-ene-3,17-dione, 4-OHA, 83) is the most studied steroidal aromatase inhibitor introduced into the market as an intramuscular formulation for the treatment of advanced breast cancer in postmenopausal women (Stein et al., 1990). Its efficacy is comparable to aminogluthimide and it is devoid of side-effects (Brodie et al., 1987). Its LD50 and LD10 values are 4.325gkg−1 and 2.9 g kg−1, respectively (Coombes et al., 1984).
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4-OHA is a strong inhibitor of aromatase but not of desmolase (Brodie et al., 1977). In contrast to aminoglutethimide, 4-OHA binding to aromatase is irreversible (Brodie et al., 1981).
In a clinical study, intramuscular injection of 4-OHA (500 mg) to 11 postmenopausal women with advanced breast cancer, caused reduction of serum estradiol for at least one week in all patients. The only side-effects observed were pain at the injection site and hot flushes (Coombes et al., 1984).
The acetyl derivative of 4-OHA has also been found to be a potent inhibitor of human placental aromatase and caused regression of 7,12-dimethylben-zanthracene (DMBA) induced tumours in rats (Brodie et al., 1979, 1982).
Minamistane (4-aminoandrosta-1,4,6-triene-3,17-dione, FCE 24928, 84) was selected from a series of 4-amino-androstene-dione derivatives as a novel irreversible aromatase inhibitor (Di Salle et al., 1990). It caused time-dependent inhibition of human placental aromatase with Ki of 50 nM. This compound was found to be more potent than 4-OHA in rats for microsomal ovarian aromatase activity. In immature rats FCE 24928 did not show any intrinsic androgenic activity unto 100 mg kg−1 day−1 s.c.
Carmen Avendaño, J. Carlos Menéndez, in Medicinal Chemistry of Anticancer Drugs, 2008
4.2.2 4-Hydroxyandrostenedione derivatives
The main representative of this group is this drug. This compound was first described as a competitive inhibitor, but subsequent evidence proved that its binding to aromatase was irreversible. The presence of the C-19 methyl group is essential, since the 19-nor derivative is not an aromatase inactivator, and this suggests that the 19-oxygenated metabolites are the inactivating species. The 4-hydroxy group is also essential, and the ethers and esters of formestane at O-4 are inactive. One possible mechanism that is consistent with these observations is summarized in Fig. 3.18, although the low activity found for the formyl derivative 3.28 proposed as an intermediate would seem to cast doubt on this proposal.
This drug 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. Formestane is also a prohormone of 4-hydroxytestosterone, an active steroid with weak androgenic activity and mild aromatase inhibitor activity. It is listed as a prohibited substance by the World Anti-Doping Agency for use in athletes.
This drug has poor oral bioavailability, and thus must be administered fortnightly (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.
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. 
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. 
Mechanism of action
This drug 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.
This drug 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.
This drug 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. 
Volume of distribution
Vd = 1.8 L/kg; widely distributed to organs and tissues when delivered intravenously. 
Protein bindingNot AvailableMetabolism
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.
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Route of elimination
Renal elimination. >95% in urine, <5% in feces.
Terminal plasma elimination half life of 18 minutes, when delivered intravenously. 
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. 
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.