Formation of reactive metabolites of benzbromarone in humanized-liver mice
Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved..
Benzbromarone, a uricosuric drug, has the potential to cause serious hepatotoxicity. Several studies have shown the formation of reactive metabolites of benzbromarone and their association with hepatotoxicity in mice. However, it is unknown whether those reactive metabolites are generated in humans in vivo. In the present study, we firstly investigated the pharmacokinetic profiles of benzbromarone in chimeric TK-NOG mice transplanted with human hepatocytes (humanized-liver mice) and then investigated whether reactive metabolites could be generated. The area under the plasma concentration-time curve ratio of benzbromarone and its major metabolites (benzbromarone: 1'-hydroxy benzbromarone: 6-hydroxy benzbromarone) in humanized-liver mice was 1: 1.2: 0.7, which was similar to that reported in humans. In addition, glutathione conjugates and their further metabolites derived from the epoxidation of the benzofuran ring and 1',6-dihydroxylation of benzbromarone were detected in the livers, urine and plasma. Furthermore, their peak intensities in mass spectrometry showed markedly higher levels compared with those of TK-NOG mice. These results suggested that the metabolic profiles of benzbromarone in humanized-liver mice were similar to those in humans and that the reactive metabolites detected in humanized-liver mice could be generated and are associated with the benzbromarone-induced hepatotoxicity in humans.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:47 |
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| Enthalten in: |
Drug metabolism and pharmacokinetics - 47(2022) vom: 15. Dez., Seite 100467 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cho, Naoki [VerfasserIn] |
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| Links: |
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| Themen: |
4POG0RL69O |
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| Anmerkungen: |
Date Completed 05.12.2022 Date Revised 05.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.dmpk.2022.100467 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM347388450 |
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| 520 | |a Benzbromarone, a uricosuric drug, has the potential to cause serious hepatotoxicity. Several studies have shown the formation of reactive metabolites of benzbromarone and their association with hepatotoxicity in mice. However, it is unknown whether those reactive metabolites are generated in humans in vivo. In the present study, we firstly investigated the pharmacokinetic profiles of benzbromarone in chimeric TK-NOG mice transplanted with human hepatocytes (humanized-liver mice) and then investigated whether reactive metabolites could be generated. The area under the plasma concentration-time curve ratio of benzbromarone and its major metabolites (benzbromarone: 1'-hydroxy benzbromarone: 6-hydroxy benzbromarone) in humanized-liver mice was 1: 1.2: 0.7, which was similar to that reported in humans. In addition, glutathione conjugates and their further metabolites derived from the epoxidation of the benzofuran ring and 1',6-dihydroxylation of benzbromarone were detected in the livers, urine and plasma. Furthermore, their peak intensities in mass spectrometry showed markedly higher levels compared with those of TK-NOG mice. These results suggested that the metabolic profiles of benzbromarone in humanized-liver mice were similar to those in humans and that the reactive metabolites detected in humanized-liver mice could be generated and are associated with the benzbromarone-induced hepatotoxicity in humans | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Benzbromarone | |
| 650 | 4 | |a Hepatotoxicity | |
| 650 | 4 | |a Humanized-liver mice | |
| 650 | 4 | |a Reactive metabolites | |
| 650 | 7 | |a Benzbromarone |2 NLM | |
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| 700 | 1 | |a Kamimura, Hidetaka |e verfasserin |4 aut | |
| 700 | 1 | |a Ohe, Tomoyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Fumi |e verfasserin |4 aut | |
| 700 | 1 | |a Akita, Hidetaka |e verfasserin |4 aut | |
| 700 | 1 | |a Kobayashi, Kaoru |e verfasserin |4 aut | |
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