Hentrozole Mechanism of Action

Pharmacology: In postmenopausal women, estrogens are mainly derived from the action of aromatase enzyme, which converts adrenal androgens to estrone and estradiol. Letrozole is a nonsteroidal aromatase inhibitor. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Pharmacokinetics: Absorption: Letrozole is rapidly and completely absorbed from the GIT and absorption is not affected by food. Steady-state plasma concentration is reached in 2-6 weeks after daily 2.5-mg dosing. Plasma concentrations at steady-state are 1.5-2 times higher than the concentrations measured after a single dose, indicating a slight nonlinearity in the pharmacokinetics. However, these steady-state levels were maintained over extended periods and continuous accumulation of letrozole does not occur.
Distribution: Letrozole is weakly protein-bound and has a large volume of distribution.
Clearance: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was 2 unidentified metabolites and 6% was unchanged letrozole. Letrozole's terminal elimination t_½ is about 2 days.
Special Populations: Pediatric, Elderly and Race: In the study populations (adults ranging from 35 to >80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.
Renal Insufficiency: In a study of volunteers with varying renal function (24-hr CrCl: 9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of letrozole 2.5 mg tablets was found. In addition, in a study of 347 patients with advanced breast cancer, about ½ of whom received letrozole 2.5 mg tablets and ½ with 0.5 mg tablets, renal impairment (calculated CrCl: 20-50 mL/min) did not affect steady-state plasma letrozole concentration.
Hepatic Insufficiency: In a study of subjects with varying degrees of non-metastatic hepatic dysfunction (eg, cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired hepatic function. Patients with severe hepatic impairment (Child-Pugh classification C) have not been studied (see Dosage & Administration).