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Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats
Pro-inflammatory factors are important indicators for assessing inflammation severity and drug efficacy. Coptisine has been reported to inhibit LPS-induced TNF-α and NO production. In this study, we aim to build a pharmacokinetic-pharmacodynamic model to quantify the coptisine time course and potenc...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363730/ https://www.ncbi.nlm.nih.gov/pubmed/30723253 http://dx.doi.org/10.1038/s41598-018-38164-4 |
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author | Hu, Yingfan Wang, Li Xiang, Li Wu, Jiasi Huang, Wen’ge Xu, Chensi Meng, Xianli Wang, Ping |
author_facet | Hu, Yingfan Wang, Li Xiang, Li Wu, Jiasi Huang, Wen’ge Xu, Chensi Meng, Xianli Wang, Ping |
author_sort | Hu, Yingfan |
collection | PubMed |
description | Pro-inflammatory factors are important indicators for assessing inflammation severity and drug efficacy. Coptisine has been reported to inhibit LPS-induced TNF-α and NO production. In this study, we aim to build a pharmacokinetic-pharmacodynamic model to quantify the coptisine time course and potency of its anti-inflammatory effect in LPS-stimulated rats. The plasma and lung coptisine concentrations, plasma and lung TNF-α concentrations, plasma NO concentration, and lung iNOS expression were measured in LPS-stimulated rats after intravenous injection of three coptisine doses. The coptisine disposition kinetics were described by a two-compartment model. The coptisine distribution process from the plasma to the lung was described by first-order dynamics. The dynamics of plasma TNF-α generation and elimination followed zero-order kinetics and the Michaelis-Menten equation. A first-order kinetic model described the TNF-α diffusion process from the plasma to the lung. A precursor-pool indirect response model was used to describe the iNOS and NO generation induced by TNF-α. The inhibition rates of TNF-α production by coptisine (54.73%, 26.49%, and 13.25%) calculated from the simulation model were close to the decline rates of the plasma TNF-α AUC (57.27%, 40.33%, and 24.98%, respectively). Coptisine suppressed plasma TNF-α generation in a linear manner, resulting in a cascading reduction of iNOS and NO. The early term TNF-α response to stimulation is a key factor in the subsequent inflammatory cascade. In conclusion, this comprehensive PK-PD model provided a rational explanation for the interlocking relationship among TNF-α, iNOS and NO production triggered by LPS and a quantitative evaluation method for inhibition of TNF-α production by coptisine. |
format | Online Article Text |
id | pubmed-6363730 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63637302019-02-07 Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats Hu, Yingfan Wang, Li Xiang, Li Wu, Jiasi Huang, Wen’ge Xu, Chensi Meng, Xianli Wang, Ping Sci Rep Article Pro-inflammatory factors are important indicators for assessing inflammation severity and drug efficacy. Coptisine has been reported to inhibit LPS-induced TNF-α and NO production. In this study, we aim to build a pharmacokinetic-pharmacodynamic model to quantify the coptisine time course and potency of its anti-inflammatory effect in LPS-stimulated rats. The plasma and lung coptisine concentrations, plasma and lung TNF-α concentrations, plasma NO concentration, and lung iNOS expression were measured in LPS-stimulated rats after intravenous injection of three coptisine doses. The coptisine disposition kinetics were described by a two-compartment model. The coptisine distribution process from the plasma to the lung was described by first-order dynamics. The dynamics of plasma TNF-α generation and elimination followed zero-order kinetics and the Michaelis-Menten equation. A first-order kinetic model described the TNF-α diffusion process from the plasma to the lung. A precursor-pool indirect response model was used to describe the iNOS and NO generation induced by TNF-α. The inhibition rates of TNF-α production by coptisine (54.73%, 26.49%, and 13.25%) calculated from the simulation model were close to the decline rates of the plasma TNF-α AUC (57.27%, 40.33%, and 24.98%, respectively). Coptisine suppressed plasma TNF-α generation in a linear manner, resulting in a cascading reduction of iNOS and NO. The early term TNF-α response to stimulation is a key factor in the subsequent inflammatory cascade. In conclusion, this comprehensive PK-PD model provided a rational explanation for the interlocking relationship among TNF-α, iNOS and NO production triggered by LPS and a quantitative evaluation method for inhibition of TNF-α production by coptisine. Nature Publishing Group UK 2019-02-05 /pmc/articles/PMC6363730/ /pubmed/30723253 http://dx.doi.org/10.1038/s41598-018-38164-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Hu, Yingfan Wang, Li Xiang, Li Wu, Jiasi Huang, Wen’ge Xu, Chensi Meng, Xianli Wang, Ping Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats |
title | Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats |
title_full | Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats |
title_fullStr | Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats |
title_full_unstemmed | Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats |
title_short | Pharmacokinetic-Pharmacodynamic Modeling for Coptisine Challenge of Inflammation in LPS-Stimulated Rats |
title_sort | pharmacokinetic-pharmacodynamic modeling for coptisine challenge of inflammation in lps-stimulated rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363730/ https://www.ncbi.nlm.nih.gov/pubmed/30723253 http://dx.doi.org/10.1038/s41598-018-38164-4 |
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