Formation of reactive metabolites of benzbromarone in humanized-liver mice

Naoki Cho, Hiroshi Suemizu, Hidetaka Kamimura, Tomoyuki Ohe, Fumi Ito, Hidetaka Akita, Kaoru Kobayashi

研究成果: Article査読

抄録

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.

本文言語English
論文番号100467
ジャーナルDrug Metabolism And Pharmacokinetics
47
DOI
出版ステータスPublished - 2022 12月

ASJC Scopus subject areas

  • 薬理学
  • 薬科学
  • 薬理学(医学)

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