RATIONALE Ibrutinib is a potent Bruton's tyrosine kinase inhibitor which has shown promising efficacy against various B-cell malignancies. Its metabolic profiles have not been disclosed. The aim of this study was to investigate the metabolism of ibrutinib in the hepatocytes of rat, dog and human. METHODS Ibrutinib was incubated with hepatocytes at 37°C for 2 h, after which the samples were analyzed using ultrahigh-performance liquid chromatography with diode-array detection and Q-Exactive Orbitrap tandem mass spectrometry (UHPLC/DAD-Q-Exactive-Orbitrap-MS). The acquired data were processed using MetWorks™ software. RESULTS A total of 20 metabolites were structurally identified by their MS and MS2 data. M1 and M5 were unambiguously identified using authentic standards. The biotransformation of ibrutinib involved hydroxylation, hydration, oxygenation, epoxide hydrolysis, dehydrogenation, dealkylation and GSH conjugation. CONCLUSIONS Humans have a relatively low capability for metabolizing ibrutinib. Compared with rat, dog had closer metabolic profiles to humans and would be more suitable for toxicity studies. This study provides more valuable information with respect to the in vitro disposition of ibrutinib.

中文翻译：

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液相色谱结合二极管阵列检测和Q-Exactive Orbitrap串联质谱在大鼠，狗和人肝细胞中对ibrutinib的体外代谢

RATIONALE依鲁替尼是一种强力的布鲁顿酪氨酸激酶抑制剂，已显示出对各种B细胞恶性肿瘤的有效疗效。其代谢概况尚未公开。本研究的目的是研究依鲁替尼在大鼠，犬和人的肝细胞中的代谢。方法将依鲁替尼与肝细胞在37°C下孵育2小时，然后使用超高效液相色谱-二极管阵列检测和Q-Exactive Orbitrap串联质谱（UHPLC / DAD-Q-Exactive-Orbitrap-小姐）。使用MetWorks™软件处理获取的数据。结果通过其MS和MS2数据在结构上鉴定了20种代谢物。M1和M5使用真实的标准明确标识。依鲁替尼的生物转化涉及羟基化，水合，氧合，环氧化物水解，脱氢，脱烷基和GSH偶联。结论人类代谢依鲁替尼的能力相对较低。与大鼠相比，狗的代谢谱更接近人类，因此更适合于毒性研究。这项研究提供了有关依鲁替尼的体外处置的更多有价值的信息。