Rapid intestinal glucuronidation and hepatic glucuronide recycling contributes significantly to the enterohepatic circulation of icaritin and its glucuronides in vivo
Icaritin (ICT), a prenylflavonoid derivative extracted from the Epimedium genus, has exhibited antitumor effects in hepatocellular carcinoma (HCC) cells and safety and tolerance in clinical settings. However, ICT exhibits low blood concentration and the in vivo dominant plasma species of ICT is glucuronides [icaritin-3-glucuronide (G1), icaritin-7-glucuronide (G2) and icaritin-3, 7-diglucuronide (DIG)]. Therefore, how ICT reaches the liver and exerts its effect with low toxicity remains unknown. Therefore, pharmacokinetic experiments (p.o. 5 mg/kg with/out 50 mg/kg inhibitor combo), intestinal perfusion (2 μM ICT), portal vein infusion (1.6 μM ICT, 7.1 μM G1, 6.8 μM G2 and 4.4 μM DIG), and in vitro studies (the concentration range of substrates: 0.3-10 μM) were conducted in the present study. Ultimately, ICT was shown to undergo glucuronidation by the intestine and subsequent uptake by hepatocytes via organic anion transporting peptides (OATPs) as conjugates, followed by biliary excretion mainly as diglucuronide. In conclusion, we found for the first time that the intestine is considered as the major metabolic organ, liver as the main recycling organ for the enterohepatic recycling (EHR) of ICT. Moreover, DIG is the main species in the systemic circulation following oral administration of ICT which explains the low toxicity of ICT in clinical settings.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:94 |
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| Enthalten in: |
Archives of toxicology - 94(2020), 11 vom: 02. Nov., Seite 3737-3749 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rong, Yi [VerfasserIn] |
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| Links: |
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| Themen: |
Diglucuronidation |
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| Anmerkungen: |
Date Completed 06.08.2021 Date Revised 24.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00204-020-02867-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM314902317 |
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| 245 | 1 | 0 | |a Rapid intestinal glucuronidation and hepatic glucuronide recycling contributes significantly to the enterohepatic circulation of icaritin and its glucuronides in vivo |
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| 500 | |a Date Revised 24.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Icaritin (ICT), a prenylflavonoid derivative extracted from the Epimedium genus, has exhibited antitumor effects in hepatocellular carcinoma (HCC) cells and safety and tolerance in clinical settings. However, ICT exhibits low blood concentration and the in vivo dominant plasma species of ICT is glucuronides [icaritin-3-glucuronide (G1), icaritin-7-glucuronide (G2) and icaritin-3, 7-diglucuronide (DIG)]. Therefore, how ICT reaches the liver and exerts its effect with low toxicity remains unknown. Therefore, pharmacokinetic experiments (p.o. 5 mg/kg with/out 50 mg/kg inhibitor combo), intestinal perfusion (2 μM ICT), portal vein infusion (1.6 μM ICT, 7.1 μM G1, 6.8 μM G2 and 4.4 μM DIG), and in vitro studies (the concentration range of substrates: 0.3-10 μM) were conducted in the present study. Ultimately, ICT was shown to undergo glucuronidation by the intestine and subsequent uptake by hepatocytes via organic anion transporting peptides (OATPs) as conjugates, followed by biliary excretion mainly as diglucuronide. In conclusion, we found for the first time that the intestine is considered as the major metabolic organ, liver as the main recycling organ for the enterohepatic recycling (EHR) of ICT. Moreover, DIG is the main species in the systemic circulation following oral administration of ICT which explains the low toxicity of ICT in clinical settings | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Diglucuronidation | |
| 650 | 4 | |a Enterohepatic recycling (EHR) | |
| 650 | 4 | |a Hepatocellular carcinoma (HCC) | |
| 650 | 4 | |a Icaritin | |
| 650 | 7 | |a Flavonoids |2 NLM | |
| 650 | 7 | |a Glucuronides |2 NLM | |
| 650 | 7 | |a Organic Anion Transporters |2 NLM | |
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| 700 | 1 | |a Dou, Guifang |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Ming |e verfasserin |4 aut | |
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