Endmet Mechanism of Action

Pharmacology: Leuprorelin acetate is a long-acting GnrH analog. A single monthly injection of leuprorelin acetate results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprorelin acetate is not active when given orally. Intramuscular injection of the depot formulation provides plasma concentrations of leuprorelin over a period of one month.
Pharmacokinetics: Absorption: A single dose of leuprorelin acetate was administered by intramuscular injection to healthy female volunteers. The absorption of leuprorelin was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/ml at four hours post dosing. However, intact leuprorelin and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprorelin concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/ml.
Distribution: The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism: In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprorelin was shown to be metabolized to smaller inactive peptides, a pentapeptide (metabolite I), tripeptides (metabolites II and Ill) and a dipeptide (metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprorelin concentrations.
Excretion: Following administration of Prolide to 3 patients. less than 5% of the dose was recovered as parent and M-i metabolite in the urine.