Wroński Michał, Trawiński Jakub, Skibiński Robert
Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland.
Pharmaceutics. 2023 Nov 4;15(11):2586. doi: 10.3390/pharmaceutics15112586.
Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound.
了解药物化合物的代谢是确保其在临床使用中的安全性和有效性的基本前提。然而,传统的药物代谢监测方法往往存在耗时且成本高的缺点。在不断寻求创新方法的过程中,电化学在代谢研究中的应用作为一种用于药物转化产物合成和分析的有前景的方法而备受关注。在本研究中,我们通过利用人肝微粒体(HLM)分析结合液相色谱-质谱联用技术,研究了抗真菌药物伏立康唑的肝脏代谢。基于所得结果,优化了电化学参数以模拟生物转化反应。在测试的各种电极中,化学计量学分析表明,铁(II)酞菁电极在催化所有肝脏伏立康唑代谢物的形成方面最为有效。这些发现例证了酞菁电极作为模拟药物生物转化中复杂代谢过程的高效且经济高效工具的潜力,为药物研究领域提供了新的可能性。此外,计算机模拟分析表明,两种检测到的代谢物可能比母体化合物表现出明显更高的急性毒性和诱变潜力。