Letrozole

Mechanism of Action

Letrozole is a potent and highly specific nonsteroidal aromatase inhibitor. It works by binding to the haem of the cytochrome P450 part of the aromatase enzyme, which blocks the enzyme's action and cuts down estrogen production in all tissues. Letrozole's antitumour effect comes from starving estrogen-dependent breast cancer cells of the growth signal they need. In postmenopausal women, most estrogen comes from the aromatase enzyme, which converts adrenal androgens, mainly androstenedione and testosterone, into oestrone (E1) and oestradiol (E2). Blocking this enzyme specifically can reduce estrogen production in the peripheral tissues and in malignant tissues alike.

In healthy postmenopausal women, single doses of 0.1, 0.5 and 2.5 mg of letrozole lower serum oestrone and oestradiol by 75-78% and 78% from baseline respectively. The strongest suppression is reached within 48 to 78 hours. In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg lower plasma oestradiol, oestrone and oestrone sulphate by 78-95% from baseline in all patients treated. In healthy postmenopausal women, letrozole had no effect on plasma androgen levels (androstenedione and testosterone) after single doses of 0.1, 0.5 and 2.5 mg. This suggests that blocking estrogen production does not cause androgenic precursors to build up. No impairment of adrenal steroidogenesis has been seen.

Pharmacokinetics

Letrozole is absorbed quickly and completely from the gut, with an absolute bioavailability of 99.9%. Food slows absorption a little, but the total amount absorbed stays the same. This small effect on the speed of absorption is not thought to matter clinically, so letrozole can be taken before, with or after food. About 60% of letrozole binds to plasma proteins, mostly albumin (55%). Its concentration in red blood cells is about 80% of that in plasma. The main way the body clears letrozole is by converting it to a pharmacologically inactive carbinol metabolite. This process is fairly slow compared with blood flow through the liver. In the laboratory, the cytochrome P450 isoenzymes 3A4 and 2A6 can convert letrozole to this metabolite, but how much each one contributes in the body has not been established. The apparent terminal elimination half-life in plasma is about 2 days. With daily doses of 2.5 mg, steady-state levels are reached within 2 to 6 weeks.