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Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound

YZG-331, a synthetic adenosine derivative, express the sedative and hypnotic effects via binding to the adenosine receptor. The current study was taken to investigate the metabolic pathway of YZG-331 as well as species-specific differences in vitro. YZG-331 was reduced by 14, 11, 6, 46, and 11% with...

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Autores principales: Liu, Zhihao, Yang, Yakun, Sheng, Li, Li, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554529/
https://www.ncbi.nlm.nih.gov/pubmed/28848441
http://dx.doi.org/10.3389/fphar.2017.00527
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author Liu, Zhihao
Yang, Yakun
Sheng, Li
Li, Yan
author_facet Liu, Zhihao
Yang, Yakun
Sheng, Li
Li, Yan
author_sort Liu, Zhihao
collection PubMed
description YZG-331, a synthetic adenosine derivative, express the sedative and hypnotic effects via binding to the adenosine receptor. The current study was taken to investigate the metabolic pathway of YZG-331 as well as species-specific differences in vitro. YZG-331 was reduced by 14, 11, 6, 46, and 11% within 120 min incubation in human, monkey, dog, rat, and mouse liver microsomes (LMs), respectively. However, YZG-331 was stable in human, monkey, dog, rat, and mouse liver cytoplasm. In addition, YZG-331 was unstable in rat or mouse gut microbiota with more than 50% of prototype drug degraded within 120 min incubation. Interestingly, the systemic exposure of M2 and M3 in rats and mice treated with antibiotics were significantly decreased in the pseudo germ-free group. YZG-331 could be metabolized in rat and human liver under the catalysis of CYP enzymes, and the metabolism showed species variation. In addition, 3 phase I metabolites were identified via hydroxyl (M1), hydrolysis (M2), or hydrolysis/ hydroxyl (M3) pathway. Flavin-containing monooxygenase 1 (FMO1) and FMO3 participated in the conversion of YZG-331 in rat LMs. Nevertheless, YZG-331 expressed stability with recombinant human FMOs, which further confirmed the species variation in the metabolism. Overall, these studies suggested that YZG-331 is not stable in LMs and gut microbiota. CYP450 enzymes and FMOs mediated the metabolism of YZG-331, and the metabolic pathway showed species difference. Special attention must be paid when extrapolating data from other species to humans.
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spelling pubmed-55545292017-08-28 Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound Liu, Zhihao Yang, Yakun Sheng, Li Li, Yan Front Pharmacol Pharmacology YZG-331, a synthetic adenosine derivative, express the sedative and hypnotic effects via binding to the adenosine receptor. The current study was taken to investigate the metabolic pathway of YZG-331 as well as species-specific differences in vitro. YZG-331 was reduced by 14, 11, 6, 46, and 11% within 120 min incubation in human, monkey, dog, rat, and mouse liver microsomes (LMs), respectively. However, YZG-331 was stable in human, monkey, dog, rat, and mouse liver cytoplasm. In addition, YZG-331 was unstable in rat or mouse gut microbiota with more than 50% of prototype drug degraded within 120 min incubation. Interestingly, the systemic exposure of M2 and M3 in rats and mice treated with antibiotics were significantly decreased in the pseudo germ-free group. YZG-331 could be metabolized in rat and human liver under the catalysis of CYP enzymes, and the metabolism showed species variation. In addition, 3 phase I metabolites were identified via hydroxyl (M1), hydrolysis (M2), or hydrolysis/ hydroxyl (M3) pathway. Flavin-containing monooxygenase 1 (FMO1) and FMO3 participated in the conversion of YZG-331 in rat LMs. Nevertheless, YZG-331 expressed stability with recombinant human FMOs, which further confirmed the species variation in the metabolism. Overall, these studies suggested that YZG-331 is not stable in LMs and gut microbiota. CYP450 enzymes and FMOs mediated the metabolism of YZG-331, and the metabolic pathway showed species difference. Special attention must be paid when extrapolating data from other species to humans. Frontiers Media S.A. 2017-08-11 /pmc/articles/PMC5554529/ /pubmed/28848441 http://dx.doi.org/10.3389/fphar.2017.00527 Text en Copyright © 2017 Liu, Yang, Sheng and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Liu, Zhihao
Yang, Yakun
Sheng, Li
Li, Yan
Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound
title Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound
title_full Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound
title_fullStr Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound
title_full_unstemmed Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound
title_short Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound
title_sort interspecies variation of in vitro stability and metabolic diversity of yzg-331, a promising sedative-hypnotic compound
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554529/
https://www.ncbi.nlm.nih.gov/pubmed/28848441
http://dx.doi.org/10.3389/fphar.2017.00527
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