Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 48, 48149 Münster, Germany; International Graduate School for Battery Chemistry, Characterization, Analysis, Recycling and Application (BACCARA), University of Münster, Corrensstraße 40, 48149 Münster, Germany.
Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 48, 48149 Münster, Germany; International Graduate School for Battery Chemistry, Characterization, Analysis, Recycling and Application (BACCARA), University of Münster, Corrensstraße 40, 48149 Münster, Germany.
J Pharm Biomed Anal. 2023 Oct 25;235:115626. doi: 10.1016/j.jpba.2023.115626. Epub 2023 Aug 2.
The hypolipidemic and hypoglycemic drug benfluorex was widely applied to treat type 2 diabetes mellitus and metabolic syndrome in overweight patients since 1976. However, benfluorex was connected to multiple cases of valvular heart disease and pulmonary arterial hypertension later on. Similar adverse drug reactions were previously found to be associated to the structurally related drug fenfluramine, which was attributed to the formation of its N-deethylated metabolite norfenfluramine. Even though norfenfluramine was known to be a common metabolite of fenfluramine and benfluorex, only fenfluramine was withdrawn from European and United States markets in 1997 while benfluorex remained available until 2009. In this work, the metabolism of benfluorex is simulated by an online hyphenation of electrochemistry and mass spectrometry and the observed transformation products are further characterized using liquid chromatography and high-resolution tandem mass spectrometry. Using this approach, norfenfluramine is found to be the main electrochemical transformation product of benfluorex. Considering the knowledge about norfenfluramine toxicity, rapid metabolite screening using electrochemistry hyphenated to mass spectrometry could have been used to predict the potential of benfluorex for adverse drug reactions early on, showcasing the value of electrochemical metabolism mimicry for rapid drug safety evaluation.
自 1976 年以来，降血脂和降血糖药物苯氟雷司被广泛应用于治疗 2 型糖尿病和超重患者的代谢综合征。然而，苯氟雷司后来与多种心脏瓣膜疾病和肺动脉高压病例有关。先前发现与结构相关的药物芬氟拉明也存在类似的药物不良反应，这归因于其 N-去乙基代谢物 norfenfluramine 的形成。尽管 norfenfluramine 是芬氟拉明和苯氟雷司的常见代谢物，但在 1997 年，仅芬氟拉明从欧洲和美国市场撤出，而苯氟雷司仍可使用至 2009 年。在这项工作中，通过电化学和质谱的在线连接模拟了苯氟雷司的代谢，并用液相色谱和高分辨率串联质谱进一步表征了观察到的转化产物。使用这种方法，发现 norfenfluramine 是苯氟雷司的主要电化学转化产物。考虑到 norfenfluramine 毒性的知识，使用电化学与质谱联用的快速代谢物筛选本可以用于早期预测苯氟雷司发生不良反应的潜力，展示了电化学代谢模拟在快速药物安全性评估中的价值。
