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Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects
Objective: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects. Materials and methods: [(14)C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted s...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dustri-Verlag Dr. Karl Feistle
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564822/ https://www.ncbi.nlm.nih.gov/pubmed/26329350 http://dx.doi.org/10.5414/CP202276 |
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author | Bui, Khanh She, Fahua Hutchison, Michael Brunnström, Åsa Sostek, Mark |
author_facet | Bui, Khanh She, Fahua Hutchison, Michael Brunnström, Åsa Sostek, Mark |
author_sort | Bui, Khanh |
collection | PubMed |
description | Objective: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects. Materials and methods: [(14)C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted subjects. Blood, fecal, and urine samples were collected predose and at various intervals postdose. Naloxegol and its metabolites were quantified or identified by liquid chromatography with radiometric or mass spectrometric detection. Pharmacokinetic parameters were calculated for each subject, and metabolite identification was performed by liquid chromatography with parallel radioactivity measurement and mass spectrometry. Results: Naloxegol was rapidly absorbed, with a maximum plasma concentration (geometric mean) of 51 ng/mL reached before 2 hours after dosing. A second peak in the observed naloxegol and [(14)C] plasma concentration-time profiles was observed at ~ 3 hours and was likely due to enterohepatic recycling of parent naloxegol. Distribution to red blood cells was negligible. Metabolism of [(14)C]-naloxegol was rapid and extensive and occurred via demethylation and oxidation, dealkylation, and shortening of the polyethylene glycol chain. Mean cumulative recovery of radioactivity was 84.2% of the total dose, with ~ 68.9% recovered within 96 hours of dosing. Fecal excretion was the predominant route of elimination, with mean recoveries of total radioactivity in feces and urine of 67.7% and 16.0%, respectively. Unchanged naloxegol accounted for ~ 1/4 of the radioactivity recovered in feces. Conclusions: Naloxegol was rapidly absorbed and cleared via metabolism, with predominantly fecal excretion of parent and metabolites. |
format | Online Article Text |
id | pubmed-4564822 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Dustri-Verlag Dr. Karl Feistle |
record_format | MEDLINE/PubMed |
spelling | pubmed-45648222015-10-01 Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects Bui, Khanh She, Fahua Hutchison, Michael Brunnström, Åsa Sostek, Mark Int J Clin Pharmacol Ther Research Article Objective: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects. Materials and methods: [(14)C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted subjects. Blood, fecal, and urine samples were collected predose and at various intervals postdose. Naloxegol and its metabolites were quantified or identified by liquid chromatography with radiometric or mass spectrometric detection. Pharmacokinetic parameters were calculated for each subject, and metabolite identification was performed by liquid chromatography with parallel radioactivity measurement and mass spectrometry. Results: Naloxegol was rapidly absorbed, with a maximum plasma concentration (geometric mean) of 51 ng/mL reached before 2 hours after dosing. A second peak in the observed naloxegol and [(14)C] plasma concentration-time profiles was observed at ~ 3 hours and was likely due to enterohepatic recycling of parent naloxegol. Distribution to red blood cells was negligible. Metabolism of [(14)C]-naloxegol was rapid and extensive and occurred via demethylation and oxidation, dealkylation, and shortening of the polyethylene glycol chain. Mean cumulative recovery of radioactivity was 84.2% of the total dose, with ~ 68.9% recovered within 96 hours of dosing. Fecal excretion was the predominant route of elimination, with mean recoveries of total radioactivity in feces and urine of 67.7% and 16.0%, respectively. Unchanged naloxegol accounted for ~ 1/4 of the radioactivity recovered in feces. Conclusions: Naloxegol was rapidly absorbed and cleared via metabolism, with predominantly fecal excretion of parent and metabolites. Dustri-Verlag Dr. Karl Feistle 2015-10 2015-09-02 /pmc/articles/PMC4564822/ /pubmed/26329350 http://dx.doi.org/10.5414/CP202276 Text en © Dustri-Verlag Dr. K. Feistle http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Bui, Khanh She, Fahua Hutchison, Michael Brunnström, Åsa Sostek, Mark Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects |
title | Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects |
title_full | Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects |
title_fullStr | Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects |
title_full_unstemmed | Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects |
title_short | Absorption, distribution, metabolism, and excretion of [(14)C]-labeled naloxegol in healthy subjects |
title_sort | absorption, distribution, metabolism, and excretion of [(14)c]-labeled naloxegol in healthy subjects |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564822/ https://www.ncbi.nlm.nih.gov/pubmed/26329350 http://dx.doi.org/10.5414/CP202276 |
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