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The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

PURPOSE: Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. METHODS: We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide...

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Autores principales: Tylleskar, Ida, Skarra, Sissel, Skulberg, Arne Kristian, Dale, Ola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585821/
https://www.ncbi.nlm.nih.gov/pubmed/34327552
http://dx.doi.org/10.1007/s00228-021-03190-1
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author Tylleskar, Ida
Skarra, Sissel
Skulberg, Arne Kristian
Dale, Ola
author_facet Tylleskar, Ida
Skarra, Sissel
Skulberg, Arne Kristian
Dale, Ola
author_sort Tylleskar, Ida
collection PubMed
description PURPOSE: Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. METHODS: We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). RESULTS: Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. CONCLUSION: Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00228-021-03190-1.
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spelling pubmed-85858212021-11-15 The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers Tylleskar, Ida Skarra, Sissel Skulberg, Arne Kristian Dale, Ola Eur J Clin Pharmacol Pharmacokinetics and Disposition PURPOSE: Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. METHODS: We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). RESULTS: Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. CONCLUSION: Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00228-021-03190-1. Springer Berlin Heidelberg 2021-07-29 2021 /pmc/articles/PMC8585821/ /pubmed/34327552 http://dx.doi.org/10.1007/s00228-021-03190-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacokinetics and Disposition
Tylleskar, Ida
Skarra, Sissel
Skulberg, Arne Kristian
Dale, Ola
The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
title The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
title_full The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
title_fullStr The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
title_full_unstemmed The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
title_short The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
title_sort pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers
topic Pharmacokinetics and Disposition
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585821/
https://www.ncbi.nlm.nih.gov/pubmed/34327552
http://dx.doi.org/10.1007/s00228-021-03190-1
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