Hazard
A reproductive hazard.
Description
Exemestane was launched in US and other countries for the treatment of estrogendependent
tumors and postmenopausal breast cancer. It is a novel steroidal compound
structurally related to the natural substrate for the biosynthesis of estrogen,
androstanedione, and can be synthesized by methylidenation of androsta-1, 4-dien-
17beta-ol-3-one in 6 position then oxidation of the alcohol function. Exemestane is an
irreversible inactivator of the aromatase enzyme system, so inducing in vivo a dose-related
sustained suppression of serum estrogen and minimal endocrine activity. It is the first
steroidal representative of the third-generation of orally active aromatase inhibitors with a
highly potent and selective mechanism of action, displaying good tolerability and safety
profile. In rats with DMBA-induced mammary tumors, 10 to 100 mglkg of exemestan
administered po twice-daily for 4 weeks resulted in 76 to 88% regression. In women failing
anti-estrogen therapy with tamoxifen, this agent has demonstrated high activity in locally
advanced or metastatic disease. In addition, it may also have potential for breast cancer
prevention.
Chemical Properties
white to light yellow crystal powder
Originator
Farmitalia Carlo Erba (Italy)
Uses
An antineoplastic (hormonal)
Uses
Labeled Exemestane, intended for use as an internal standard for the quantification of Exemestane by GC- or LC-mass spectrometry.
Definition
ChEBI: A 17-oxo steroid that is androsta-1,4-diene-3,17-dione in which the hydrogens at position 6 are replaced by a double bond to a methylene group. A selective inhibitor of the aromatase (oestrogen synthase) system, it is used in the treatment of advanced brea
t cancer.
Manufacturing Process
0.50 g of 6-methylenandrost-4-ene-3,17-dione and 0.57 g of
dichlorodicyanobenzoquinone were refluxed in 20 ml of anhydrous dioxane for
about 15 hours. To remove the DDQ the suspension was filtered through
alumina. After evaporation of the solvent the residue was dissolved in ethyl
acetate, the organic layer washed with water, dried over sodium sulfate and
the solvent removed under vacuum. The crude product was chromatographed
on silica gel using hexane/ethyl acetate to yield 0.25 g of pure 6-
methylenandrosta-1,4-diene-3,17-dione, m.p. 188-191°C, λmax 247 nm (ε
13.750).
Brand name
Aromasin (Pharmacia& Upjohn).
Therapeutic Function
Antineoplastic
General Description
Exemestane, 6-methylenandrosta-1,4-diene-3,17-dione (Aromasin), is the first steroid-basedaromatase inhibitor approved for the treatment of breastcancer in the United States. It is a mechanism-based inactivatorthat irreversibly inhibits the enzyme. Plasma estrogenlevels are reduced by 85% to 95% within 2 to 3 days, and effectslast 4 to 5 days. Exemestane does not inhibit any of themajor cytochromes P450 and has essentially no interactionwith steroid receptors, with only a very weak affinity for theAR. The 17β-hydroxyexemestane reduction product, however,has much higher affinity for the AR than the parent(still several fold less than DHT, 0.28% for parent vs. 30%for metabolite). The clinical significance of the affinity islikely minimal because of the low levels of the metaboliteproduced.
Biochem/physiol Actions
Exemestane is a steroidal antiestrogen and irreversible aromatase inhibitor. Exemestane acts as a false substrate for the aromatase enzyme. Exemestane also prevents the conversion of androgens to estrogens and is used to treat estrogen-dependent breast cancer.
Clinical Use
Irreversible, steroidal aromatase inhibitor:Treatment of breast cancer
Metabolism
Metabolised via oxidation by the cytochrome
P450 isoenzyme CYP3A4, and via reduction by
aldoketoreductase. Metabolites are excreted in the urine
(39-45%) and faeces (36-48%).
References
[1] franco buzzetti, enrico di salle, antonio longo, gabriella briatico. synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione). steroids. november 1993. 58(11): 527-532.
[2] gustavo de albuquerque cavalcanti, bruno carius garrido, felipe dias leal, monica costa padilha, xavier de la torre, francisco radler de aquino neto. detection of new urinary exemestane metabolites by gas chromatography coupled to mass spectrometry. steroids. september–october 2011. 76(10-11): 1010-1015.
[3] stephanie a. jones, stephen e. jones. exemestane: a novel aromatase inactivator for breast cancer. clinical breast cancer. october 2000. 1(3): 211-216.
