Chira Ruxandra, Fangmeyer Jens, Neaga Ioan O, Zaharia Valentin, Karst Uwe, Bodoki Ede, Oprean Radu
Analytical Chemistry Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400349, Cluj-Napoca, Romania.
University of Münster, Institute of Inorganic and Analytical Chemistry, 48149, Münster, Germany.
J Pharm Anal. 2021 Oct;11(5):661-666. doi: 10.1016/j.jpha.2021.03.011. Epub 2021 Apr 1.
Considering the frequent use of netupitant in polytherapy, the elucidation of its oxidative metabolization pattern is of major importance. However, there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist. Therefore, this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method. Most of the known enzyme-mediated reactions occurring in the liver (i.e., -dealkylation, hydroxylation, and -oxidation) were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode. The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry. Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications, this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.
鉴于奈妥吡坦在联合治疗中的频繁使用，阐明其氧化代谢模式至关重要。然而，关于这种新型神经激肽-1受体拮抗剂的氧化还原行为，目前尚无公开的研究报道。因此，本研究采用电化学驱动方法模拟奈妥吡坦在肝脏中的强烈生物转化过程。肝脏中发生的大多数已知酶介导反应（即脱烷基化、羟基化和氧化反应）均能通过使用掺硼金刚石工作电极的电解池成功模拟。产物通过反相高效液相色谱法分离，并通过高分辨率质谱法进行鉴定。除了能够精确识别可能导致奈妥吡坦已知副作用或与未来治疗适应症的任何新观点相关的先前未知代谢物外，这种电化学过程还为合成氧化产物以供进一步的体外和体内研究提供了一种简便的替代方法。
