Degarelix is a decapeptide that shows high affinity/selectivity to human gonadotropin-releasing hormone receptors and have been approved for the treatment of advanced prostate cancer in US, EU and Japan.
To investigate the metabolism of degarelix in humans, in vitro metabolism was addressed in liver tissue and in vivo metabolism was studied in plasma and excreta samples collected in clinical studies. Also, drug transporter interaction potential of degarelix with selected efflux transporters and uptake transporters was studied using in vitro membrane vesicles based assays and whole cell based assays. In vitro degradation was observed in fresh hepatocytes, less than 25 % of the initial concentration of degarelix remained after incubation at 37°C for 2 hours. One metabolite was detected representing a truncated nonapeptide of degarelix. The same metabolite was also detected at low concentrations in plasma. The in vivo investigations also showed that degarelix is excreted unchanged via the urine, but is undergoing extensive sequential peptidic degradation during its elimination via the hepato-biliary pathway. No unique human metabolites of degarelix were detected in the circulation or in the excreta. Degarelix did not show any interaction with selected efflux transporters and uptake transporters up to concentrations representing 200 times the clinical concentration. Since degarelix does not seem to interact with the CYP450 enzyme system as substrate, inhibitor or inducer, and does not show any interaction with hepatic and renal uptake and efflux transporters the risk for pharmacokinetic drug-drug interactions with this compound is highly unlikely.
Written by:
Sonesson A, Buur Rasmussen B. Are you the author?
Ferring Pharmaceuticals A/S.
Reference: Drug Metab Dispos. 2013 Apr 15. Epub ahead of print.
doi: 10.1124/dmd.113.051706
PubMed Abstract
PMID: 23589543
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