Metabolite Profiles of Degarelix, a New Gonadotropin-Releasing Hormone Receptor Antagonist, in Rat, Dog, and Monkey

Abstract

ABSTRACT:Degarelix is a novel competitive gonadotropin-releasing hormone receptor blocker (antagonist). In this study, the nonclinical metabolism and excretion of degarelix was investigated in SpragueDawley rat, beagle dog, and cynomolgus monkey. Degarelix was found to be stable when incubated in microsomes and cryopreserved hepatocytes from animal liver tissue. Absorption, distribution, metabolism, and excretion studies in male rat, dog, and monkey showed that after a subcutaneous dose of tritium-labeled degarelix, the peptide was rapidly absorbed with C max in plasma of 1 to 2 h. The predominant route of excretion was via the kidneys and the bile. In rat and dog, most of the degarelix dose was eliminated within 48 h via urine and feces in equal amounts (40-50% in each matrix), whereas in monkey the major route of excretion was fecal (50%) and renal (22%). In plasma and urine samples from all three species, mainly intact degarelix was detected. In bile and feces samples from rats and dogs, the same truncated peptides of the parent decapeptide were detected. The major metabolites identified represented the N-terminal tetrapeptide, the pentapeptide, and the heptapeptide. From the animal studies, it could be concluded that degarelix is subject to common peptidic degradation in the liver and bile and is fully excreted via metabolic and biliary (as metabolites and parent compound) and urinary (mainly as parent compound) pathways. Systemic exposure to metabolic products seems to be low.

Investigation of the GnRH antagonist degarelix isomerization in biological matrices

“…Thus, the origin of the nonapeptide in plasma samples could be due to the enzymatic degradation by endopeptidases located in the hepatic tissue 29 . Metabolite pattern study allowed the detection of N‐terminal tetra‐ and penta‐peptides as main fragments formed during the passage of the hepatobiliary system 31 …”

“… 29 Metabolite pattern study allowed the detection of N‐terminal tetra‐ and penta‐peptides as main fragments formed during the passage of the hepatobiliary system. 31 …”

“…29 Metabolite pattern study allowed the detection of N-terminal tetra-and penta-peptides as main fragments formed during the passage of the hepatobiliary system. 31 In previous studies of degarelix metabolism, chromatographic cates that the transformation of degarelix in vivo could be rather fast if compared with the rate of the release of the peptide from the depot to reach the maximum concentration in the blood (61.0-71.0 ng/mL in 37-42 h after starting dose injection) and leads to a decrease of the concentration of the circulating peptide. 32 In this case, the contribution of the dihydroorotate-hydantoin isomerization mediated by the slightly basic physiologic pH is negligible, as demonstrated by the experiments in phosphate buffer and human serum albumin solutions.…”

Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer

“…[10,26,27,30] Degarelix undergoes degradation by the hepato-biliary system but is fully excreted by both hepatic and renal mechanisms. [31] Degarelix has not been evaluated in those with renal impairment. Prescribing information at this time states it does not require dose adjustment in those with mild renal impairment but should be use with caution in those with moderate or severe impairment.…”