4.2 Article

Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes

期刊

XENOBIOTICA
卷 51, 期 5, 页码 582-589

出版社

TAYLOR & FRANCIS LTD
DOI: 10.1080/00498254.2021.1875515

关键词

Tolbutamide; humanised-liver mouse; Hu-Liver cell; species difference; oxidative metabolism

资金

  1. Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED [20am0101121j0004]
  2. Japan Society for the Promotion of Science [20K06463]
  3. METI Artificial Intelligence-based Substance Hazard Integrated Prediction System project, Japan
  4. Grants-in-Aid for Scientific Research [20K06463] Funding Source: KAKEN

向作者/读者索取更多资源

This study investigated tolbutamide metabolism in chimeric TK-NOG mice transplanted with human hepatocytes, showing that humanised-liver mice may be a suitable animal model for studying the successive oxidative metabolism of tolbutamide by multiple drug-metabolising enzymes.
Tolbutamide is an oral anti-hyperglycaemic agent used to treat non-insulin-dependent diabetes mellitus with species-dependent metabolic profiles. In this study, we investigated tolbutamide metabolism in chimeric TK-NOG mice transplanted with human hepatocytes (humanised-liver mice). Substantial 4-hydroxytolbutamide and 4-carboxytolbutamide production was observed in hepatocytes from humanised-liver mice (Hu-Liver cells) and humans, whereas 4-carboxytolbutamide production was not detected in mouse hepatocytes. In Hu-Liver cells, 4-hydroxytolbutamide formation was inhibited by sulfaphenazole (CYP2C9 inhibitor), whereas 4-carboxytolbutamide formation was inhibited by raloxifene/ethinyloestradiol (aldehyde oxidase inhibitor) and disulfiram (aldehyde dehydrogenase inhibitor). After a single oral dose of tolbutamide (10 mg/kg), the plasma levels of 4-carboxytolbutamide and p-tolylsulfonylurea were higher in humanised-liver mice than in TK-NOG mice. Urinary excretion was the predominant route (>99% of unchanged drug and metabolites detected in excreta) of elimination in both groups. 4-Carboxytolbutamide was the most abundant metabolite in humanised-liver mouse urine, as similarly reported for humans, whereas 4-hydroxytolbutamide was predominantly excreted in TK-NOG mouse urine. These results suggest that humanised-liver mice might represent a suitable animal model for studying the successive oxidative metabolism of tolbutamide by multiple drug-metabolising enzymes. Future work is warranted to study the general nature of primary alcohol metabolism using humanised-liver mice.

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