Simulation of the oxidative metabolization pattern of netupitant, an NK1 receptor antagonist, by electrochemistry coupled to mass spectrometry

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., N-dealkylation, hydroxylation, and Noxidation) 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. (c) 2021 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study successfully simulated the oxidative metabolization pattern of netupitant in the liver using an electrochemically driven method. The electrolytic cell mimicked known enzyme-mediated reactions, and the products were identified using high-performance liquid chromatography and mass spectrometry. This electrochemical process not only helps discover unknown metabolites of netupitant but also provides a convenient alternative for further research on therapeutic indications.