RATIONALE TUG-891 is a potent and selective agonist of the long chain free fatty acid receptor 4. However, its metabolic profiles have not been revealed. The aim of this study was to investigate the in vitro metabolism of TUG-891 in hepatocytes. METHODS TUG-891 at a concentration of 20 μM was incubated with rat, dog, and human hepatocytes at 37°C for 120 min. The samples were analyzed using ultra-high-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry. The structures of the metabolites were proposed according to their MS/MS product ions. Furthermore, M4 and M5 were biosynthesized using human liver microsomes, and their structures were characterized using 13 C-NMR spectroscopy. RESULTS Under the current conditions, eight metabolites were detected and structurally identified using high-resolution LC/MS and MS/MS spectra. The metabolites M4 and M5 were unambiguously confirmed to be TUG-891 alcohol and TUG-891 acid, respectively, using 13 C-NMR spectroscopy. Our results revealed that hydroxylation of methyl group at C-21 position to form TUG-891 alcohol (M5) followed by oxidation to yield TUG-891 aldehyde (M7) and carboxylic acid (M4) were the major metabolism processes. Phase II metabolism processes included glucuronidation and sulphation. CONCLUSIONS Hydroxylation at the C-21 position was the primary metabolic site of TUG-891. This study provided an overview of the metabolic profiles of TUG-891 in hepatocytes.

中文翻译：

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使用超高效液相色谱串联质谱和核磁共振波谱表征大鼠，狗和人肝细胞中TUG-891的代谢产物。

RATIONALE TUG-891是长链游离脂肪酸受体4的有效和选择性激动剂。但是，尚未揭示其代谢特征。这项研究的目的是调查肝细胞中TUG-891的体外代谢。方法将浓度为20μM的TUG-891与大鼠，狗和人的肝细胞在37°C下孵育120分钟。使用超高效液相色谱结合电喷雾电离串联质谱分析样品。根据其MS / MS产物离子提出了代谢物的结构。此外，使用人肝微粒体生物合成了M4和M5，并使用13 C-NMR光谱对其结构进行了表征。结果在当前条件下，使用高分辨率LC / MS和MS / MS光谱检测并在结构上鉴定了8种代谢物。使用13 C-NMR光谱法明确地确认代谢物M4和M5分别为TUG-891醇和TUG-891酸。我们的结果表明，甲基在C-21位羟基化形成TUG-891醇（M5），然后氧化生成TUG-891醛（M7）和羧酸（M4）是主要的代谢过程。II期代谢过程包括葡萄糖醛酸化和硫酸化。结论C-21位的羟基化是TUG-891的主要代谢位点。这项研究概述了TUG-891在肝细胞中的代谢特征。使用13 C-NMR光谱。我们的结果表明，甲基在C-21位羟基化形成TUG-891醇（M5），然后氧化生成TUG-891醛（M7）和羧酸（M4）是主要的代谢过程。II期代谢过程包括葡萄糖醛酸化和硫酸化。结论C-21位的羟化是TUG-891的主要代谢位点。这项研究概述了TUG-891在肝细胞中的代谢特征。使用13 C-NMR光谱。我们的结果表明，甲基在C-21位羟基化形成TUG-891醇（M5），然后氧化生成TUG-891醛（M7）和羧酸（M4）是主要的代谢过程。II期代谢过程包括葡萄糖醛酸化和硫酸化。结论C-21位的羟基化是TUG-891的主要代谢位点。这项研究概述了TUG-891在肝细胞中的代谢特征。结论C-21位的羟基化是TUG-891的主要代谢位点。这项研究概述了TUG-891在肝细胞中的代谢特征。结论C-21位的羟基化是TUG-891的主要代谢位点。这项研究概述了TUG-891在肝细胞中的代谢特征。