AI - exemestane (Aromasin)

Hi Opale:

The "irreversible" mechanism of action of exemestane (AROMASIN) has come up elsewhere and caused some confusion. The "irreversible" mechanism of action does not mean that the action of exemestane cannot be thwarted by discontinuing the drug or that it has a permanent effect. If it were truly "irreversible" in a layperson sense, you wouldn't need to take it for so long.

Per their FDA labels, all three Aromatase Inhibitors (AIs) are provided in the form of tablets for oral administration. The different mechanisms of action of steroidal versus non-steroidal AIs are not based on differences in drug delivery, but are a consequence of the different molecular structures of the drug substances and how they interact with the aromatase enzyme.

Regarding the biochemical mechanism of action of exemestane, the FDA label for the drug explains:

"Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate 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 . . ."

Per one recent review article:

"Many of the most widely employed and successful drugs in clinical use are irreversible drugs.[1-8] Aspirin, which was developed by Bayer in 1897 as an anti-inflammatory agent, is probably the best known example. As with many other examples, the covalent mechanism of action of Aspirin was discovered by serendipity more than 70 years after its commercialization. Aspirin causes the irreversible inhibition of cyclooxygenases 1 (COX-1) and 2 (COX-2), which are enzymes involved in the prostaglandin biosynthesis, by acylation of a serine residue that is close to the active site.[9, 10] Other examples are penicillins and cephalosporins,[7] which are antibiotics that inhibit the cross-linking of bacterial cell walls catalyzed by penicillin binding proteins (Figure 1). Fosfomycin,[11-13] which is an antibiotic that targets MurA, an enzyme involved in peptidoglycan biosynthesis, and omeprazole, which is a proton pump inhibitor for the treatment of diverse stomach diseases, are further examples.[14]"

By becoming stably bound to its enzyme target, an "irreversible" inhibitor acts in a one-on-one manner. While drug therapy continues, prolonged duration of inhibition of the bound enzyme is theoretically possible. However, once drug is discontinued, free drug levels decrease according to half-life. Exemestane has "a mean terminal half-life of about 24 hours" in healthy post-menopausal women: it takes a few days to get rid of free drug. Meanwhile, aromatase activity will recover via the synthesis of new aromatase enzyme molecules. As for any remaining inhibitor that is irreversibly stuck to one enzyme molecule, it cannot go get another aromatase enzyme molecule, so any newly synthesized aromatase enzyme is free to do its business, unless you resume treatment with an AI.

BarredOwl

Opale:

Were you pre- or post-menopausal at diagnosis?

BarredOwl