Pharmacokinetics and Metabolite Profiling of Trepibutone in Rats Using Ultra-High Performance Liquid Chromatography Combined With Hybrid Quadrupole-Orbitrap and Triple Quadrupole Mass Spectrometers
Pharmacokinetics and Metabolite Profiling of Trepibutone in Rats Using Ultra-High Performance Liquid Chromatography Combined With Hybrid Quadrupole-Orbitrap and Triple Quadrupole Mass Spectrometers
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DOI：
10.3389/fphar.2019.01266
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发表时间：
2019-11
影响因子：
5.6
通讯作者：
Zhi Sun;Jie Yang;Li-wei Liu;Yanyan Xu;Lin Zhou;Qing‐quan Jia;Yingying Shi;Xiangyu Du;Jian Kang;Lihua Zuo
中科院分区：
文献类型：
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作者：
Zhi Sun;Jie Yang;Li-wei Liu;Yanyan Xu;Lin Zhou;Qing‐quan Jia;Yingying Shi;Xiangyu Du;Jian Kang;Lihua Zuo
曲匹布通在临床上广泛用于治疗胆石症、胆囊炎、胆道运动障碍、胆囊切除综合征、慢性胰腺炎等。然而，对曲匹布酮的研究很少。本研究建立了一种准确、灵敏、选择性好的曲匹布酮在大鼠体内的药代动力学分析方法。采用多反应监测（MRM）模式，分别在m/z 311.09→265.08和m/z 237.06→194.08的跃迁下定量测定曲匹布酮和卡马西平（内标，IS）。所建立的方法的线性、精密度、准确度、提取回收率、基质效应和稳定性均在可接受范围内。通过Q-Exactive高分辨质谱分析，在血浆和尿液中共鉴定出30种代谢产物，并观察到脱烷基化、氧化、还原、葡萄糖醛酸化等常见代谢途径，为临床合理使用曲匹布酮提供了更多的药效学和毒理学信息。
Trepibutone was widely used for cholelithiasis, cholecystitis, biliary tract dyskinesia, cholecystectomy syndrome, and chronic pancreatitis in clinic. However, few investigations on trepibutone have been conducted. In this study, an accurate, sensitive, and selective analytical method was developed and successfully applied to assess the pharmacokinetic behavior of trepibutone in rats. Trepibutone and carbamazepine (internal standard, IS) were quantified using multiple reaction monitoring (MRM) mode with the transitions of m/z 311.09→265.08 and m/z 237.06→194.08, respectively. The linearity, precision, accuracy, extraction recovery, matrix effect, and stability of the established method were all excellent within acceptable range. A total of 30 metabolites were identified in plasma and urine by Q-Exactive high resolution mass spectrometry, and several common metabolic pathways were observed such as dealkylation, oxidation, reduction, glucuronidation, and so on. This research provides more information on trepibutone in pharmacodynamics and toxicology and will assist the usage of trepibutone in clinical.