Letoripe Mechanism of Action

Pharmacology: Mechanism of Action: Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. It inhibits the conversion of androgens to estrogens. In adult, nontumor- 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 to ovariectomy, treatment with Letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Pharmacodynamics: The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e. 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 androgens primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissues itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
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 biosynthesis in all 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 metabolized 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 the 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, 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 pharmaceutically 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 radio label covered 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 enzymes activity, CYP 3A4 metabolized Letrozole to the carbotinol metabolite while CYP 2A6 formed both the metabolite and its ketoanalogue. In human liver microsomes, Letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.
Toxicology: Preclinical safety data: In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of systemic or target organ toxicity. Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs, Letrozole caused signs of moderate toxicity at 100 mg/kg.
In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings observed can be attributed to the pharmacological action of the compound. The no-adverse-effect level was 0.3 mg/kg in both species.
Both in vitro and in vivo investigations of Letrozole's mutagenic potential revealed no indications of any genotoxicity.
In a 104-week rat carcinogenicity study, no treatment-related tumours were noted in male rats. In female rats, a reduced incidence of benign and malignant mammary tumours at all the doses of Letrozole was found.
Letrozole was embryotoxic and foetotoxic in pregnant rats and rabbits following oral administration at clinically relevant doses. In rats that had live foetuses, there was an increase in the incidence of foetal malformations including domed head and cervical/centrum vertebral fusion. An increased incidence of foetal malformations was not seen in the rabbit. It is not known whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a direct drug effect.
Preclinical observations were confined to those associated with the recognized pharmacological action, which is the only safety concern for human use derived from animal studies.