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Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity

Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry (Morus alba L., genus Morus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evid...

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Autores principales: Liu, Zhihua, Feng, Yu, Zhao, Hang, Hu, Jinping, Chen, Yanmin, Liu, Dongdong, Wang, Hongliang, Zhu, Xiangyang, Yang, Hongzhen, Shen, Zhufang, Xia, Xuejun, Ye, Jun, Liu, Yuling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981942/
https://www.ncbi.nlm.nih.gov/pubmed/36873997
http://dx.doi.org/10.3389/fphar.2023.1136772
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author Liu, Zhihua
Feng, Yu
Zhao, Hang
Hu, Jinping
Chen, Yanmin
Liu, Dongdong
Wang, Hongliang
Zhu, Xiangyang
Yang, Hongzhen
Shen, Zhufang
Xia, Xuejun
Ye, Jun
Liu, Yuling
author_facet Liu, Zhihua
Feng, Yu
Zhao, Hang
Hu, Jinping
Chen, Yanmin
Liu, Dongdong
Wang, Hongliang
Zhu, Xiangyang
Yang, Hongzhen
Shen, Zhufang
Xia, Xuejun
Ye, Jun
Liu, Yuling
author_sort Liu, Zhihua
collection PubMed
description Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry (Morus alba L., genus Morus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evidence has confirmed that SZ-A exerts multiple pharmacological effects, such as protecting pancreatic ß-cell function, stimulating adiponectin expression, and alleviating hepatic steatosis. Importantly, a specific distribution of SZ-A in target tissues following oral absorption into the blood is essential for the induction of multiple pharmacological effects. However, there is a lack of studies thoroughly exploring the pharmacokinetic profiles and tissue distribution of SZ-A following oral absorption into the blood, particularly dose-linear pharmacokinetics and target tissue distribution associated with glycolipid metabolic diseases. In the present study, we systematically investigated the pharmacokinetics and tissue distribution of SZ-A and its metabolites in human and rat liver microsomes, and rat plasma, as well as its effects on the activity of hepatic cytochrome P450 enzymes (CYP450s). The results revealed that SZ-A was rapidly absorbed into the blood, exhibited linear pharmacokinetic characteristics in the dose range of 25–200 mg/kg, and was broadly distributed in glycolipid metabolism-related tissues. The highest SZ-A concentrations were observed in the kidney, liver, and aortic vessels, followed by the brown and subcutaneous adipose tissues, and the heart, spleen, lung, muscle, pancreas, and brain. Except for the trace oxidation products produced by fagomine, other phase I or phase II metabolites were not detected. SZ-A had no inhibitory or activating effects on major CYP450s. Conclusively, SZ-A is rapidly and widely distributed in target tissues, with good metabolic stability and a low risk of triggering drug-drug interactions. This study provides a framework for deciphering the material basis of the multiple pharmacological functions of SZ-A, its rational clinical use, and the expansion of its indications.
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spelling pubmed-99819422023-03-04 Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity Liu, Zhihua Feng, Yu Zhao, Hang Hu, Jinping Chen, Yanmin Liu, Dongdong Wang, Hongliang Zhu, Xiangyang Yang, Hongzhen Shen, Zhufang Xia, Xuejun Ye, Jun Liu, Yuling Front Pharmacol Pharmacology Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry (Morus alba L., genus Morus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evidence has confirmed that SZ-A exerts multiple pharmacological effects, such as protecting pancreatic ß-cell function, stimulating adiponectin expression, and alleviating hepatic steatosis. Importantly, a specific distribution of SZ-A in target tissues following oral absorption into the blood is essential for the induction of multiple pharmacological effects. However, there is a lack of studies thoroughly exploring the pharmacokinetic profiles and tissue distribution of SZ-A following oral absorption into the blood, particularly dose-linear pharmacokinetics and target tissue distribution associated with glycolipid metabolic diseases. In the present study, we systematically investigated the pharmacokinetics and tissue distribution of SZ-A and its metabolites in human and rat liver microsomes, and rat plasma, as well as its effects on the activity of hepatic cytochrome P450 enzymes (CYP450s). The results revealed that SZ-A was rapidly absorbed into the blood, exhibited linear pharmacokinetic characteristics in the dose range of 25–200 mg/kg, and was broadly distributed in glycolipid metabolism-related tissues. The highest SZ-A concentrations were observed in the kidney, liver, and aortic vessels, followed by the brown and subcutaneous adipose tissues, and the heart, spleen, lung, muscle, pancreas, and brain. Except for the trace oxidation products produced by fagomine, other phase I or phase II metabolites were not detected. SZ-A had no inhibitory or activating effects on major CYP450s. Conclusively, SZ-A is rapidly and widely distributed in target tissues, with good metabolic stability and a low risk of triggering drug-drug interactions. This study provides a framework for deciphering the material basis of the multiple pharmacological functions of SZ-A, its rational clinical use, and the expansion of its indications. Frontiers Media S.A. 2023-02-17 /pmc/articles/PMC9981942/ /pubmed/36873997 http://dx.doi.org/10.3389/fphar.2023.1136772 Text en Copyright © 2023 Liu, Feng, Zhao, Hu, Chen, Liu, Wang, Zhu, Yang, Shen, Xia, Ye and Liu. 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
Liu, Zhihua
Feng, Yu
Zhao, Hang
Hu, Jinping
Chen, Yanmin
Liu, Dongdong
Wang, Hongliang
Zhu, Xiangyang
Yang, Hongzhen
Shen, Zhufang
Xia, Xuejun
Ye, Jun
Liu, Yuling
Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
title Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
title_full Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
title_fullStr Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
title_full_unstemmed Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
title_short Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
title_sort pharmacokinetics and tissue distribution of ramulus mori (sangzhi) alkaloids in rats and its effects on liver enzyme activity
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981942/
https://www.ncbi.nlm.nih.gov/pubmed/36873997
http://dx.doi.org/10.3389/fphar.2023.1136772
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