Lebreta Mechanism of Action

Pharmacology: Pharmacodynamics: The growth of some cancers of the breast is stimulated or maintained by estrogens. The elimination of oestrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to oestrone (E1) and oestradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. As a result, letrozole interferes with estrogen-induced stimulation or maintenance of growth of hormonally responsive (estrogen and/or progesterone receptor positive or receptor unknown) breast cancers.
Letrozole is a non-steroidal aromatase inhibitor and is highly specific in inhibiting aromatase activity. It inhibits the aromatase enzyme by competitively binding to the haem group of aromatase, a cytochrome P450 enzyme which catalyzes conversion of androgens to estrogens (specifically, androstenedione to estrone and testosterone to estradiol) resulting in a significant reduction of oestrogen biosynthesis in peripheral tissues and cancer tissue. Aromatase inhibition by letrozole appears to be specific, with sparing of other cytochrome P450 enzymes of the same class involved in glucocorticoid and mineralocorticoid synthesis.
There is no changes in plasma concentrations of androgens (androstenedione and testosterone) or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of letrozole indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by letrozole in patients, nor are thyroid function as evaluated by TSH, T4 and T3 uptake.
Pharmacokinetics: Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract. Food decreases the rate but not the extent of absorption.
Distribution: Letrozole is rapidly and extensively distributed to tissues.
Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). Its apparent volume of distribution at steady state is about 1.87 ± 0.47 L/kg.
Metabolism and Elimination: In vitro data suggest that it is metabolised by the cytochrome P450 isoenzymes CYP3A4 and CYP2A6. Most of an oral dose is slowly metabolised to an inactive carbinol metabolite, which is then excreted as the glucuronide in the urine. Letrozole has a terminal elimination half-life of about 2 days, and steady-state concentrations occur within 2 to 6 weeks. Age had no effect on the pharmacokinetics of letrozole.