Letoripe Mechanism of Action







Full Prescribing Info
Pharmacology: Mechanism of action: The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (ie. Estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy or inhibit estrogen effects antiestrogens and progestational agents) these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
In postmenopausal women estrogens are mainly derived from the action of the aromatase enzyme which converts adrenal endrogens primarily androstenedione and testosterone 0 to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in cancer tissues itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non steroidal competitive inhibitor of the aromatase enzyme system, it inhibits the conversion of androgens to estrogens. In adult non tumor and tumor bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH and causing the regression of estrogen dependent tumors. In contrast with ovariectomy treatment with letrozole does not lead to an increase in serum. FSH. Letrozole selectively inhibits gonadal steroidgenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme resulting in a reduction of estrogen bio synthesis of the tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis or synthesis of thyroid hormones.
Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolised slowly to an inactive metabolite whose glucuronide conjugate is excreted renally representing the major clearance pathway. About 90% of the radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half life is about 2 days and steady state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from then concentrations measured after a single dose indicating a slight non-linearity in the pharmacokinetics of Letrozole upon daily administration of 2.5 mg . These steady state levels are maintained over extended periods however and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).
Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanolbisbenzonitrile) 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 two unidentified metabolites, and 6% was unchanged letrozole.
In human microsomes with specific CYP isozymes activity, CYP 3A4 metabolized letrozole to the carbotinol metabolite while CYP 2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.
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