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Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice

PMX53 and PMX205 are cyclic hexapeptide inhibitors of complement C5a receptors (C5aR1), that are widely used to study C5aR1 pathobiology in mouse models of disease. Despite their widespread use, limited information regarding their pharmacokinetics have been reported. Here, a bioanalytical method for...

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Autores principales: Kumar, Vinod, Lee, John D., Clark, Richard J., Woodruff, Trent M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970165/
https://www.ncbi.nlm.nih.gov/pubmed/29802264
http://dx.doi.org/10.1038/s41598-018-26387-4
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author Kumar, Vinod
Lee, John D.
Clark, Richard J.
Woodruff, Trent M.
author_facet Kumar, Vinod
Lee, John D.
Clark, Richard J.
Woodruff, Trent M.
author_sort Kumar, Vinod
collection PubMed
description PMX53 and PMX205 are cyclic hexapeptide inhibitors of complement C5a receptors (C5aR1), that are widely used to study C5aR1 pathobiology in mouse models of disease. Despite their widespread use, limited information regarding their pharmacokinetics have been reported. Here, a bioanalytical method for the quantitative determination of PMX53 and PMX205 in plasma, brain and spinal cord of mice was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. The LC-MS/MS method was validated in all three matrices according to regulatory guidelines and successfully applied to pharmacokinetic studies of PMX53 and PMX205 in C57BL/6 J mice following intravenous administration. The developed method was highly sensitive and sufficiently accurate with a lower limit of quantification within the range of 3–6 ng/ml in extracted plasma samples and 3–6 ng/g in processed tissue samples, which outperforms previously published LC-MS/MS methods. The results thus support the suitability, reliability, reproducibility and sensitivity of this validated technique. This method can therefore be applied to perform a complete pre-clinical investigation of PMX53 and PMX205 pharmacokinetics in mice.
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spelling pubmed-59701652018-05-30 Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice Kumar, Vinod Lee, John D. Clark, Richard J. Woodruff, Trent M. Sci Rep Article PMX53 and PMX205 are cyclic hexapeptide inhibitors of complement C5a receptors (C5aR1), that are widely used to study C5aR1 pathobiology in mouse models of disease. Despite their widespread use, limited information regarding their pharmacokinetics have been reported. Here, a bioanalytical method for the quantitative determination of PMX53 and PMX205 in plasma, brain and spinal cord of mice was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. The LC-MS/MS method was validated in all three matrices according to regulatory guidelines and successfully applied to pharmacokinetic studies of PMX53 and PMX205 in C57BL/6 J mice following intravenous administration. The developed method was highly sensitive and sufficiently accurate with a lower limit of quantification within the range of 3–6 ng/ml in extracted plasma samples and 3–6 ng/g in processed tissue samples, which outperforms previously published LC-MS/MS methods. The results thus support the suitability, reliability, reproducibility and sensitivity of this validated technique. This method can therefore be applied to perform a complete pre-clinical investigation of PMX53 and PMX205 pharmacokinetics in mice. Nature Publishing Group UK 2018-05-25 /pmc/articles/PMC5970165/ /pubmed/29802264 http://dx.doi.org/10.1038/s41598-018-26387-4 Text en © The Author(s) 2018 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kumar, Vinod
Lee, John D.
Clark, Richard J.
Woodruff, Trent M.
Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
title Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
title_full Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
title_fullStr Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
title_full_unstemmed Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
title_short Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
title_sort development and validation of a lc-ms/ms assay for pharmacokinetic studies of complement c5a receptor antagonists pmx53 and pmx205 in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970165/
https://www.ncbi.nlm.nih.gov/pubmed/29802264
http://dx.doi.org/10.1038/s41598-018-26387-4
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