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Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the pre...

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Autores principales: Yuan, Yawen, Li, Zhihong, Wang, Ke, Zhang, Shunguo, He, Qingfeng, Liu, Lucy, Tang, Zhijia, Zhu, Xiao, Chen, Ying, Cai, Weimin, Peng, Chao, Xiang, Xiaoqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866629/
https://www.ncbi.nlm.nih.gov/pubmed/36677893
http://dx.doi.org/10.3390/molecules28020837
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author Yuan, Yawen
Li, Zhihong
Wang, Ke
Zhang, Shunguo
He, Qingfeng
Liu, Lucy
Tang, Zhijia
Zhu, Xiao
Chen, Ying
Cai, Weimin
Peng, Chao
Xiang, Xiaoqiang
author_facet Yuan, Yawen
Li, Zhihong
Wang, Ke
Zhang, Shunguo
He, Qingfeng
Liu, Lucy
Tang, Zhijia
Zhu, Xiao
Chen, Ying
Cai, Weimin
Peng, Chao
Xiang, Xiaoqiang
author_sort Yuan, Yawen
collection PubMed
description Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01–1.0 μg/mL. The free drug fraction (f(u)) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (C(max)) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.
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spelling pubmed-98666292023-01-22 Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model Yuan, Yawen Li, Zhihong Wang, Ke Zhang, Shunguo He, Qingfeng Liu, Lucy Tang, Zhijia Zhu, Xiao Chen, Ying Cai, Weimin Peng, Chao Xiang, Xiaoqiang Molecules Article Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01–1.0 μg/mL. The free drug fraction (f(u)) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (C(max)) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development. MDPI 2023-01-13 /pmc/articles/PMC9866629/ /pubmed/36677893 http://dx.doi.org/10.3390/molecules28020837 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
Yuan, Yawen
Li, Zhihong
Wang, Ke
Zhang, Shunguo
He, Qingfeng
Liu, Lucy
Tang, Zhijia
Zhu, Xiao
Chen, Ying
Cai, Weimin
Peng, Chao
Xiang, Xiaoqiang
Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
title Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
title_full Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
title_fullStr Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
title_full_unstemmed Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
title_short Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
title_sort pharmacokinetics of novel furoxan/coumarin hybrids in rats using lc-ms/ms method and physiologically based pharmacokinetic model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866629/
https://www.ncbi.nlm.nih.gov/pubmed/36677893
http://dx.doi.org/10.3390/molecules28020837
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