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Biotransformation of Penindolone, an Influenza A Virus Inhibitor

Penindolone (PND) is a novel broad-spectrum anti-Influenza A Virus (IAV) agent blocking hemagglutinin-mediated adsorption and membrane fusion. The goal of this work was to reveal the metabolic route of PND in rats. Ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry...

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Autores principales: Liu, Shuai, Zheng, Keming, Jiang, Yilin, Gai, Susu, Li, Bohan, Li, Dehai, Yang, Shuang, Lv, Zhihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9920254/
https://www.ncbi.nlm.nih.gov/pubmed/36771146
http://dx.doi.org/10.3390/molecules28031479
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author Liu, Shuai
Zheng, Keming
Jiang, Yilin
Gai, Susu
Li, Bohan
Li, Dehai
Yang, Shuang
Lv, Zhihua
author_facet Liu, Shuai
Zheng, Keming
Jiang, Yilin
Gai, Susu
Li, Bohan
Li, Dehai
Yang, Shuang
Lv, Zhihua
author_sort Liu, Shuai
collection PubMed
description Penindolone (PND) is a novel broad-spectrum anti-Influenza A Virus (IAV) agent blocking hemagglutinin-mediated adsorption and membrane fusion. The goal of this work was to reveal the metabolic route of PND in rats. Ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC–HRMS) was used for metabolite identification in rat bile, feces and urine after administration of PND. A total of 25 metabolites, including 9 phase I metabolites and 16 phase II metabolites, were characterized. The metabolic pathways were proposed, and metabolites were visualized via Global Natural Product Social Molecular Networking (GNPS). It was found that 65.24–80.44% of the PND presented in the formation of glucuronide conjugate products in bile, and more than 51% of prototype was excreted through feces. In in vitro metabolism of PND by rat, mouse and human liver microsomes (LMs) system, PND was discovered to be eliminated in LMs to different extents with significant species differences. The effects of chemical inhibitors of isozymes on the metabolism of PND in vitro indicated that CYP2E1/2C9/3A4 and UGT1A1/1A6/1A9 were the metabolic enzymes responsible for PND metabolism. PND metabolism in vivo could be blocked by UGTs inhibitor (ibrutinib) to a certain extent. These findings provided a basis for further research and development of PND.
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spelling pubmed-99202542023-02-12 Biotransformation of Penindolone, an Influenza A Virus Inhibitor Liu, Shuai Zheng, Keming Jiang, Yilin Gai, Susu Li, Bohan Li, Dehai Yang, Shuang Lv, Zhihua Molecules Article Penindolone (PND) is a novel broad-spectrum anti-Influenza A Virus (IAV) agent blocking hemagglutinin-mediated adsorption and membrane fusion. The goal of this work was to reveal the metabolic route of PND in rats. Ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC–HRMS) was used for metabolite identification in rat bile, feces and urine after administration of PND. A total of 25 metabolites, including 9 phase I metabolites and 16 phase II metabolites, were characterized. The metabolic pathways were proposed, and metabolites were visualized via Global Natural Product Social Molecular Networking (GNPS). It was found that 65.24–80.44% of the PND presented in the formation of glucuronide conjugate products in bile, and more than 51% of prototype was excreted through feces. In in vitro metabolism of PND by rat, mouse and human liver microsomes (LMs) system, PND was discovered to be eliminated in LMs to different extents with significant species differences. The effects of chemical inhibitors of isozymes on the metabolism of PND in vitro indicated that CYP2E1/2C9/3A4 and UGT1A1/1A6/1A9 were the metabolic enzymes responsible for PND metabolism. PND metabolism in vivo could be blocked by UGTs inhibitor (ibrutinib) to a certain extent. These findings provided a basis for further research and development of PND. MDPI 2023-02-03 /pmc/articles/PMC9920254/ /pubmed/36771146 http://dx.doi.org/10.3390/molecules28031479 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Shuai
Zheng, Keming
Jiang, Yilin
Gai, Susu
Li, Bohan
Li, Dehai
Yang, Shuang
Lv, Zhihua
Biotransformation of Penindolone, an Influenza A Virus Inhibitor
title Biotransformation of Penindolone, an Influenza A Virus Inhibitor
title_full Biotransformation of Penindolone, an Influenza A Virus Inhibitor
title_fullStr Biotransformation of Penindolone, an Influenza A Virus Inhibitor
title_full_unstemmed Biotransformation of Penindolone, an Influenza A Virus Inhibitor
title_short Biotransformation of Penindolone, an Influenza A Virus Inhibitor
title_sort biotransformation of penindolone, an influenza a virus inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9920254/
https://www.ncbi.nlm.nih.gov/pubmed/36771146
http://dx.doi.org/10.3390/molecules28031479
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