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Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist
DL0410, a dual-action cholinesterase inhibitor and histamine-3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method f...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625456/ https://www.ncbi.nlm.nih.gov/pubmed/31173186 http://dx.doi.org/10.3892/mmr.2019.10306 |
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author | Pang, Xiaocong Zhao, Ying Song, Junke Kang, De Wu, Song Wang, Lin Liu, Ailin Du, Guanhua |
author_facet | Pang, Xiaocong Zhao, Ying Song, Junke Kang, De Wu, Song Wang, Lin Liu, Ailin Du, Guanhua |
author_sort | Pang, Xiaocong |
collection | PubMed |
description | DL0410, a dual-action cholinesterase inhibitor and histamine-3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatography-mass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquid-liquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment. |
format | Online Article Text |
id | pubmed-6625456 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-66254562019-07-31 Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist Pang, Xiaocong Zhao, Ying Song, Junke Kang, De Wu, Song Wang, Lin Liu, Ailin Du, Guanhua Mol Med Rep Articles DL0410, a dual-action cholinesterase inhibitor and histamine-3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatography-mass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquid-liquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment. D.A. Spandidos 2019-08 2019-05-28 /pmc/articles/PMC6625456/ /pubmed/31173186 http://dx.doi.org/10.3892/mmr.2019.10306 Text en Copyright: © Pang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Pang, Xiaocong Zhao, Ying Song, Junke Kang, De Wu, Song Wang, Lin Liu, Ailin Du, Guanhua Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
title | Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
title_full | Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
title_fullStr | Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
title_full_unstemmed | Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
title_short | Pharmacokinetics, excretion and metabolites analysis of DL0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
title_sort | pharmacokinetics, excretion and metabolites analysis of dl0410, a dual-acting cholinesterase inhibitor and histamine-3 receptor antagonist |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625456/ https://www.ncbi.nlm.nih.gov/pubmed/31173186 http://dx.doi.org/10.3892/mmr.2019.10306 |
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