Abstract

1. 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).

2. 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).

3. 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.

4. 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.

摘要

1. 甲苯磺丁胺是一种口服抗高血糖药，用于治疗具有物种依赖性代谢特征的非胰岛素依赖性糖尿病。在这项研究中，我们调查了移植人肝细胞的嵌合TK-NOG小鼠中的甲苯磺丁酰胺代谢（人源化肝小鼠）。

2. 在来自人源化肝小鼠（Hu-Liver细胞）和人的肝细胞中观察到大量的4-羟基甲苯丁酰胺和4-羧基甲苯丁酰胺生成，而在小鼠肝细胞中未检测到4-羧基甲苯丁酰胺生成。在Hu-Liver细胞中，磺胺苯并恶唑（CYP2C9抑制剂）抑制了4-羟基甲苯丁酰胺的形成，而雷洛昔芬/乙炔雌二醇（醛氧化酶抑制剂）和双硫仑（醛脱氢酶抑制剂）抑制了4-羧基甲苯丁酰胺的形成。

3. 单次口服甲苯磺丁酰胺（10 mg / kg）后，人源化肝小鼠的4-羧基甲苯丁酰胺和对甲苯磺酰脲的血浆水平高于TK-NOG小鼠。尿排泄是两组的主要清除途径（排泄物中检出的未清除药物和代谢物的> 99％）。如人类报告的一样，4-羧甲苯丁酰胺是人源化肝小鼠尿液中最丰富的代谢物，而TK-NOG小鼠尿液中主要排泄有4-羟基甲苯磺丁酰胺。

4. 这些结果表明，人源化肝脏小鼠可能代表一种合适的动物模型，用于研究多种药物代谢酶对甲苯磺丁酰胺的连续氧化代谢。将来有必要研究使用人源化肝小鼠的伯醇代谢的一般性质。