to body surface area). Interactions Exemestane is metabolized by the liver enzyme CYP3A4. While the CYP3A4 inhibitor ketoconazole had no significant effect on exemestane levels in a clinical trial, the strong CYP3A4 inductor rifampicin significantly cut exemenstane levels about in half (AUC −54%, Cmax −41% for a single dose), potentially compromising its effectiveness. Other 3A4 inductors such as carbamazepine and St John's Wort are expected to have similar effects. The clinical relevance of this effect has not been investigated. Estrogens probably reduce exemestane effectiveness: It would usually be counter-productive to reduce the body's estrogen synthesis with exemestane and then substitute estrogen with pharmaceuticals. Pharmacology Pharmacodynamics Exemestane is an oral steroidal aromatase inhibitor that is used in ER-positive breast cancer in addition to surgery and/or radiation in post-menopausal women. The main source of estrogen is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced via the conversion of androgens into estrogen by the aromatase enzyme in the peripheral tissues (i.e. adipose tissue like that of the breast) and a number of sites in the brain. Estrogen is produced locally via the actions of the aromatase enzyme in these peripheral tissues where it acts locally. Any circulating estrogen in post-menopausal women as well as men is the result of estrogen escaping local metabolism and entering the circulatory system. Exemestane is an irreversible, steroidal aromatase inactivator of type I, structurally related to the natural substrate 4-androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." By being structurally similar to enzyme targets, exemestane permanently binds to the enzymes, preventing them from converting androgen into estrogen. Type II aromatase inhibitors such as anastrozole and letrozole, by contrast, are not steroids and work by interfering with the aromatase's heme. A study conducted on young adult males found that the estrogen suppression rate for exemestane varied from 35% for estradiol (E2) to 70% for estrone (E1). Pharmacokinetics Exemestane is quickly absorbed from the gut, but undergoes a strong first-pass effect in the liver. Highest blood plasma concentrations are reached after 1.2 hours in breast cancer patients and after 2.9 hours in healthy subjects. Maximal aromatase inhibition occurs after two to three days. 90% of the absorbed substance are bound to plasma proteins.