Simulation of sildenafil metabolism using an electrochemical oxidation system

Drug metabolism studies play a pivotal role in drug development, as they help predict the toxicity of newly developed drugs. Traditional approaches for drug metabolism studies often utilize cytochrome P450 systems, such as liver microsomes and hepatocytes. Recently, electrochemical oxidation systems have emerged as a promising alternative, capable of simulating phase I metabolic reactions, including hydroxylation, N-dealkyation, S-oxidation, P-oxidation, and dehydrogenation. Additionally, mass spectrometry (MS) has become indispensable in drug metabolism research due to its ability to detect trace amounts of metabolites and elucidate the structures of unknown metabolites using tandem MS spectra. In this study, we simulated sildenafil metabolism using an electrochemical oxidation system. The similarity between metabolic profiles generated by the electrochemical oxidation system and the liver microsomal incubation system was assessed using Pearson's correlation coefficient. A total of 96 metabolites and oxidation products were detected in both systems. Among the tested conditions, the profile of oxidation products generated at the glassy carbon electrode (ammonium acetate, pH 8.0) showed the highest correlation with the metabolic profile from the human liver microsome system at 25 μmol/L of sildenafil, highlighting the ability of this electrochemical setup to effectively mimic in vitro microsomal metabolism. In conclusion, while electrochemical oxidation systems cannot entirely replace traditional in vitro metabolism models, such as liver microsomes, S9 fractions, and hepatocytes, these findings highlight the importance of EC systems as complementary tools in metabolic studies, opening new avenues for progress in drug metabolism research.