Disposition of Detirelix, A Potent Luteinizing Hormone-Releasing Hormone Antagonist, in Rats and Monkeys

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Abstract
The disposition of detirelix, a potent luteinizing hormone-releasing hormone (LHRH) antagonist, was studied in rats and monkeys. After a single 300-µg/kg intravenous dose in rats, the plasma elimination t1/2 was 1.6 hr and the plasma clearance was 3.3 ml/min/kg. In the monkey, the mean t1/2 and plasma clearance were 7.1 hr and 1.3 ml/min/kg, respectively, after an 80-µg/kg intravenous dose. Long plasma t1/2 values of 18.7 and 31.6 hr were observed after single 0.2- and 1.0-mg/kg subcutaneous doses in the monkey, suggesting the possibility of subcutaneous depot formation at the injection site. Biliary excretion was the predominant route of elimination of detirelix in both species. Less than 10% of the detirelix was excreted renally. A major metabolite, isolated from the rat bile, was the 1–4 tetrapeptide fragment of detirelix. This metabolite was formed by enzymatic hydrolysis of the Ser4–Tyr5 bond, one of the only two peptide bonds in detirelix not containing a D-amino acid.

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