Physiologically based pharmacokinetic modeling for confirming the role of CYP3A1/2 and P-glycoprotein in detoxification mechanism between glycyrrhizic acid and aconitine in rats
© 2024 John Wiley & Sons Ltd..
Fuzi, an effective common herb, is often combined with Gancao to treat disease in clinical practice with enhancing its efficacy and alleviating its toxicity. The major toxic and bioactive compounds in Fuzi and Gancao are aconitine (AC) and glycyrrhizic acid (GL), respectively. This study aims to elucidate detoxification mechanism between AC and GL from pharmacokinetic perspective using physiologically based pharmacokinetic (PBPK) model. In vitro experiments exhibited that AC was mainly metabolized by CYP3A1/2 in rat liver microsomes and transported by P-glycoprotein (P-gp) in Caco-2 cells. Kinetics assays showed that the Km and Vmax of AC towards CYP3A1/2 were 2.38 μM and 57.3 pmol/min/mg, respectively, whereas that of AC towards P-gp was 11.26 μM and 147.1 pmol/min/mg, respectively. GL markedly induced the mRNA expressions of CYP3A1/2 and MDR1a/b in rat primary hepatocytes. In vivo studies suggested that the intragastric and intravenous administration of GL significantly reduced systemic exposure of AC by 27% and 33%, respectively. Drug-drug interaction (DDI) model of PBPK predicted that co-administration of GL would decrease the exposure of AC by 39% and 45% in intragastric and intravenous dosing group, respectively. The consistency between predicted data and observed data confirmed that the upregulation of CYP3A1/2 and P-gp was the crucial detoxification mechanism between AC and GL. Thus, this study provides a demonstration for elucidating the compatibility mechanisms of herbal formula using PBPK modeling and gives support for the clinical co-medication of Fuzi and Gancao.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Journal of applied toxicology : JAT - (2024) vom: 06. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jin, Jingyi [VerfasserIn] |
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| Links: |
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| Themen: |
Aconitine |
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| Anmerkungen: |
Date Revised 06.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1002/jat.4595 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369378148 |
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| 245 | 1 | 0 | |a Physiologically based pharmacokinetic modeling for confirming the role of CYP3A1/2 and P-glycoprotein in detoxification mechanism between glycyrrhizic acid and aconitine in rats |
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| 520 | |a Fuzi, an effective common herb, is often combined with Gancao to treat disease in clinical practice with enhancing its efficacy and alleviating its toxicity. The major toxic and bioactive compounds in Fuzi and Gancao are aconitine (AC) and glycyrrhizic acid (GL), respectively. This study aims to elucidate detoxification mechanism between AC and GL from pharmacokinetic perspective using physiologically based pharmacokinetic (PBPK) model. In vitro experiments exhibited that AC was mainly metabolized by CYP3A1/2 in rat liver microsomes and transported by P-glycoprotein (P-gp) in Caco-2 cells. Kinetics assays showed that the Km and Vmax of AC towards CYP3A1/2 were 2.38 μM and 57.3 pmol/min/mg, respectively, whereas that of AC towards P-gp was 11.26 μM and 147.1 pmol/min/mg, respectively. GL markedly induced the mRNA expressions of CYP3A1/2 and MDR1a/b in rat primary hepatocytes. In vivo studies suggested that the intragastric and intravenous administration of GL significantly reduced systemic exposure of AC by 27% and 33%, respectively. Drug-drug interaction (DDI) model of PBPK predicted that co-administration of GL would decrease the exposure of AC by 39% and 45% in intragastric and intravenous dosing group, respectively. The consistency between predicted data and observed data confirmed that the upregulation of CYP3A1/2 and P-gp was the crucial detoxification mechanism between AC and GL. Thus, this study provides a demonstration for elucidating the compatibility mechanisms of herbal formula using PBPK modeling and gives support for the clinical co-medication of Fuzi and Gancao | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a P-glycoprotein | |
| 650 | 4 | |a aconitine | |
| 650 | 4 | |a cytochrome P450 3A | |
| 650 | 4 | |a glycyrrhizic acid | |
| 650 | 4 | |a physiologically based pharmacokinetic (PBPK) | |
| 700 | 1 | |a Xu, Xiaoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Fengling |e verfasserin |4 aut | |
| 700 | 1 | |a Weng, Fengyi |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Dongming |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Furong |e verfasserin |4 aut | |
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