Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS

Abstract

Establishing the metabolism pathway of the drug undergoing the hepatic biotransformation pathway is one of the most important aspects in the preclinical discovery process since the presence of toxic or reactive metabolites may result in drug withdrawal from the market. In this study, we present the structural elucidation of six, not described yet, metabolites of an antipsychotic molecule: molindone. The elucidation of metabolites was supported with a novel photocatalytical approach with the use of WO3 and WS2 assisted photochemical reactions. An UHPLC-ESI-Q-TOF combined system was used for the registration of all obtained metabolite profiles as well as to record the high resolution fragmentation spectra of the observed transformation products. As a reference in the in vitro metabolism simulation method, the incubation with human liver microsomes was used. Chemometric comparison of the obtained profiles pointed out the use of the WO3 approach as being more convenient in the field of drug metabolism studies. Moreover, the photocatalysis was used in the direction of the main drug metabolite synthesis in order to further isolation and characterization.

Photochemistry in Medicinal Chemistry and Chemical Biology

“…Similarly, photoinduced reactions such as photocatalytic oxidation have been widely used to synthesize the metabolites of drugs in an attempt to mimic phase I metabolism reactions (Figure ). − …”

Comprehensive Analysis of Pterostilbene Metabolites In Vivo and In Vitro Using a UHPLC-Q-Exactive Plus Mass Spectrometer with Multiple Data-Mining Methods

“…Recently, ultrahigh-performance liquid chromatography coupled with mass spectrometry (UHPLC–MS), especially high-resolution mass spectrometry (HRMS), combined with pattern recognition analysis has become an unbiased discrimination method to identify bioactive compounds of drugs in vivo and vitro. , In order to detect as many pterostilbene metabolites as possible, in this study, various data-processing techniques, including multiple mass defect filter (MMDF) and full scan–parent ion list–dynamic exclusion (FS-PIL-DE), were used to identify compounds in complex environments. , Additionally, diagnostic product ion (DPI) analysis could provide a criterion to judge the target constituents detected into certain chemical families . As such, structurally related compounds that are part of the same biosynthetic class often exhibit common key MS/MS fragmentation characteristics, including shared product ions and/or neutral losses .…”

Identification of the New Metabolite of Nebivolol Using Liquid Chromatography Coupled with High-Resolution Mass Spectrometry and Chemometrics

“…During the phase II reactions, the intermediates received in phase I undergo connections with the endogenous compounds (e.g., glucuronic acid) and then the excretion process takes a place. It should be noticed that the majority of the metabolic reactions are mainly catalyzed by cytochrome P450 enzymes, and thus this kind of research is often performed with the use of in vitro human liver microsomes (HLM) protocol [ 1 , 2 , 3 , 4 , 5 , 6 ].…”