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Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2
Aim: The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetic...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175024/ https://www.ncbi.nlm.nih.gov/pubmed/35694247 http://dx.doi.org/10.3389/fphar.2022.804377 |
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author | Ren, Hong-can Sun, Jian-guo A, Ji-ye Gu, Sheng-hua Shi, Jian Shao, Feng Ai, Hua Zhang, Jing-wei Peng, Ying Yan, Bei Huang, Qing Liu, Lin-sheng Sai, Yang Wang, Guang-ji Yang, Cheng-guang |
author_facet | Ren, Hong-can Sun, Jian-guo A, Ji-ye Gu, Sheng-hua Shi, Jian Shao, Feng Ai, Hua Zhang, Jing-wei Peng, Ying Yan, Bei Huang, Qing Liu, Lin-sheng Sai, Yang Wang, Guang-ji Yang, Cheng-guang |
author_sort | Ren, Hong-can |
collection | PubMed |
description | Aim: The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetics of Rh2 and PPD following intravenous and oral Rh2 administration, 2) develop and validate a mechanism-based pharmacokinetic model to describe the deglycosylation kinetics and 3) predict the percentage of Rh2 entering the systemic circulation in PPD form. Methods: Plasma samples were collected from rats after the I.V. or P.O. administration of Rh2. The plasma Rh2 and PPD concentrations were determined using HPLC-MS. The transformation from Rh2 to PPD, its absorption, and elimination were integrated into the mechanism based pharmacokinetic model to describe the pharmacokinetics of Rh2 and PPD simultaneously at 10 mg/kg. The concentration data collected following a 20 mg/kg dose of Rh2 was used for model validation. Results: Following Rh2 administration, PPD exhibited high exposure and atypical double peaks. The model described the abnormal kinetics well and was further validated using external data. A total of 11% of the administered Rh2 was predicted to be transformed into PPD and enter the systemic circulation after I.V. administration, and a total of 20% of Rh2 was predicted to be absorbed into the systemic circulation in PPD form after P.O. administration of Rh2. Conclusion: The developed model provides a useful tool to quantitatively study the deglycosylation kinetics of Rh2 and thus, provides a valuable resource for future pharmacokinetic studies of glycosides with similar deglycosylation metabolism. |
format | Online Article Text |
id | pubmed-9175024 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91750242022-06-09 Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 Ren, Hong-can Sun, Jian-guo A, Ji-ye Gu, Sheng-hua Shi, Jian Shao, Feng Ai, Hua Zhang, Jing-wei Peng, Ying Yan, Bei Huang, Qing Liu, Lin-sheng Sai, Yang Wang, Guang-ji Yang, Cheng-guang Front Pharmacol Pharmacology Aim: The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetics of Rh2 and PPD following intravenous and oral Rh2 administration, 2) develop and validate a mechanism-based pharmacokinetic model to describe the deglycosylation kinetics and 3) predict the percentage of Rh2 entering the systemic circulation in PPD form. Methods: Plasma samples were collected from rats after the I.V. or P.O. administration of Rh2. The plasma Rh2 and PPD concentrations were determined using HPLC-MS. The transformation from Rh2 to PPD, its absorption, and elimination were integrated into the mechanism based pharmacokinetic model to describe the pharmacokinetics of Rh2 and PPD simultaneously at 10 mg/kg. The concentration data collected following a 20 mg/kg dose of Rh2 was used for model validation. Results: Following Rh2 administration, PPD exhibited high exposure and atypical double peaks. The model described the abnormal kinetics well and was further validated using external data. A total of 11% of the administered Rh2 was predicted to be transformed into PPD and enter the systemic circulation after I.V. administration, and a total of 20% of Rh2 was predicted to be absorbed into the systemic circulation in PPD form after P.O. administration of Rh2. Conclusion: The developed model provides a useful tool to quantitatively study the deglycosylation kinetics of Rh2 and thus, provides a valuable resource for future pharmacokinetic studies of glycosides with similar deglycosylation metabolism. Frontiers Media S.A. 2022-05-25 /pmc/articles/PMC9175024/ /pubmed/35694247 http://dx.doi.org/10.3389/fphar.2022.804377 Text en Copyright © 2022 Ren, Sun, A, Gu, Shi, Shao, Ai, Zhang, Peng, Yan, Huang, Liu, Sai, Wang and Yang. https://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) and the copyright owner(s) 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 Ren, Hong-can Sun, Jian-guo A, Ji-ye Gu, Sheng-hua Shi, Jian Shao, Feng Ai, Hua Zhang, Jing-wei Peng, Ying Yan, Bei Huang, Qing Liu, Lin-sheng Sai, Yang Wang, Guang-ji Yang, Cheng-guang Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 |
title | Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 |
title_full | Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 |
title_fullStr | Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 |
title_full_unstemmed | Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 |
title_short | Mechanism-Based Pharmacokinetic Model for the Deglycosylation Kinetics of 20(S)-Ginsenosides Rh2 |
title_sort | mechanism-based pharmacokinetic model for the deglycosylation kinetics of 20(s)-ginsenosides rh2 |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175024/ https://www.ncbi.nlm.nih.gov/pubmed/35694247 http://dx.doi.org/10.3389/fphar.2022.804377 |
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