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Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry

Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European...

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Autores principales: Kadi, Adnan A., Amer, Sawsan M., Darwish, Hany W., Attwa, Mohamed W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953916/
https://www.ncbi.nlm.nih.gov/pubmed/29766296
http://dx.doi.org/10.1186/s13065-018-0429-y
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author Kadi, Adnan A.
Amer, Sawsan M.
Darwish, Hany W.
Attwa, Mohamed W.
author_facet Kadi, Adnan A.
Amer, Sawsan M.
Darwish, Hany W.
Attwa, Mohamed W.
author_sort Kadi, Adnan A.
collection PubMed
description Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European Medicines Agency has accepted a conditional marketing authorization application for MST to treat amyotrophic lateral sclerosis. In our work, we focused on studying in vivo metabolism of MST in Sprague–Dawley rats. Single oral dose of MST (33 mg kg(−1)) was given to Sprague–Dawley rats (kept in metabolic cages) using oral gavage. Urine was collected and filtered at 0, 6, 12, 18, 24, 48, 72 and 96 h from MST dosing. An equal amount of ACN was added to urine samples. Both organic and aqueous layers were injected into liquid chromatography-tandem mass spectrometry (LC–MS/MS) to detect in vivo phase I and phase II MST metabolites. The current work reports the identification and characterization of twenty in vivo phase I and four in vivo phase II metabolites of MST by LC–MS/MS. Phase I metabolic pathways were reduction, demethylation, hydroxylation, oxidative deamination, oxidation and N-oxide formation. Phase II metabolic pathways were the direct conjugation of MST, N-demethyl metabolites and oxidative metabolites with glucuronic acid. Part of MST dose was excreted unchanged in urine. The literature review showed no previous articles have been made on in vivo metabolism of MST or detailed structural identification of the formed in vivo phase I and phase II metabolites. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13065-018-0429-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-59539162018-05-18 Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry Kadi, Adnan A. Amer, Sawsan M. Darwish, Hany W. Attwa, Mohamed W. Chem Cent J Research Article Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European Medicines Agency has accepted a conditional marketing authorization application for MST to treat amyotrophic lateral sclerosis. In our work, we focused on studying in vivo metabolism of MST in Sprague–Dawley rats. Single oral dose of MST (33 mg kg(−1)) was given to Sprague–Dawley rats (kept in metabolic cages) using oral gavage. Urine was collected and filtered at 0, 6, 12, 18, 24, 48, 72 and 96 h from MST dosing. An equal amount of ACN was added to urine samples. Both organic and aqueous layers were injected into liquid chromatography-tandem mass spectrometry (LC–MS/MS) to detect in vivo phase I and phase II MST metabolites. The current work reports the identification and characterization of twenty in vivo phase I and four in vivo phase II metabolites of MST by LC–MS/MS. Phase I metabolic pathways were reduction, demethylation, hydroxylation, oxidative deamination, oxidation and N-oxide formation. Phase II metabolic pathways were the direct conjugation of MST, N-demethyl metabolites and oxidative metabolites with glucuronic acid. Part of MST dose was excreted unchanged in urine. The literature review showed no previous articles have been made on in vivo metabolism of MST or detailed structural identification of the formed in vivo phase I and phase II metabolites. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13065-018-0429-y) contains supplementary material, which is available to authorized users. Springer International Publishing 2018-05-15 /pmc/articles/PMC5953916/ /pubmed/29766296 http://dx.doi.org/10.1186/s13065-018-0429-y Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Kadi, Adnan A.
Amer, Sawsan M.
Darwish, Hany W.
Attwa, Mohamed W.
Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
title Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
title_full Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
title_fullStr Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
title_full_unstemmed Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
title_short Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
title_sort characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953916/
https://www.ncbi.nlm.nih.gov/pubmed/29766296
http://dx.doi.org/10.1186/s13065-018-0429-y
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