Exemestane

Absorption

42%

Toxicity

Convulsions

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-17-beta-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.

Chemical properties

white to light yellow crystal powder

Originator

Farmitalia Carlo Erba (Italy)

The Uses of Exemestane

Labeled Exemestane, intended for use as an internal standard for the quantification of Exemestane by GC- or LC-mass spectrometry.

The Uses of Exemestane

An antineoplastic (hormonal)

The Uses of Exemestane

antiinfective

Background

Exemestane is an oral steroidal aromatase inhibitor used in the adjuvant treatment of hormonally-responsive (also called hormone-receptor-positive, estrogen-responsive) breast cancer in postmenopausal women. It irreversibly binds to the active site of the enzyme resulting in permanent inhibition.

Indications

For the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

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.

Hazard

A reproductive hazard.

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.

Pharmacokinetics

Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands. The aromatase inhibitors (AIs) are drugs that reduce estrogen levels by blocking the action of aromatase in the adrenal glands. The selective AIs (SAIs) selectively reduce levels of estrogen without interfering with levels of other steroid hormones that are produced by the adrenal gland. Drugs in this class include anastrozole (Arimidex ?), letrozole (Femara ?) and exemestane (Aromasin ?).

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%).

Side Effects

Hot flashes, hair loss, bone pain, tiredness, unusual sweating, nausea, diarrhea, dizziness, and trouble sleeping may occur during taking Exemestane.

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.