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Research ArticleArticle

In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

Anders Sonesson and Birgitte Buur Rasmussen
Drug Metabolism and Disposition July 2013, 41 (7) 1339-1346; DOI: https://doi.org/10.1124/dmd.113.051706
Anders Sonesson
Ferring Pharmaceuticals A/S, Department of Bioanalysis, Copenhagen, Denmark
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Birgitte Buur Rasmussen
Ferring Pharmaceuticals A/S, Department of Bioanalysis, Copenhagen, Denmark
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Abstract

Degarelix is a decapeptide that shows high affinity/selectivity to human gonadotropin-releasing hormone receptors and has been approved for the treatment of advanced prostate cancer in the United States, European Union, 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. In addition, drug transporter interaction potential of degarelix with selected efflux transporters and uptake transporters was studied using in vitro membrane vesicle–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. Because degarelix does not seem to interact with the cytochrome P450 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.

Footnotes

    • Received February 24, 2013.
    • Accepted April 15, 2013.
  • dx.doi.org/10.1124/dmd.113.051706.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (7)
Drug Metabolism and Disposition
Vol. 41, Issue 7
1 Jul 2013
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Research ArticleArticle

In Vitro and In Vivo Metabolism of Degarelix

Anders Sonesson and Birgitte Buur Rasmussen
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1339-1346; DOI: https://doi.org/10.1124/dmd.113.051706

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Research ArticleArticle

In Vitro and In Vivo Metabolism of Degarelix

Anders Sonesson and Birgitte Buur Rasmussen
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1339-1346; DOI: https://doi.org/10.1124/dmd.113.051706
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