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.
Highlights
Molindone (3-ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydroindol-4-one) is a medicine originally and mainly used in schizophrenia treatment
It should be noted that the photocatalytic methods significantly improved the identification of the minor metabolites due to their higher abundances and better detection with the use
It should be noted that the photocatalytic methods significantly improved the identification of the minor metabolites due to their higher abundances and better detection with the use of the MS method
Summary
Molindone (3-ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydroindol-4-one) is a medicine originally and mainly used in schizophrenia treatment. The mechanism of molindone action assumes D2S , D2L , D5 dopamine, and 5-HT2B serotonin receptor antagonist activity and remains strictly in correlation with the dopamine hypothesis of schizophrenia [4,5,6,7,8,9]. It should be noted that patients treated with molindone are exposed to the occurrence of side effects, for instance, tardive dyskinesia or akathisia, according to the commonly known mechanism of neuroleptics dopamine antagonistic potential [10,11,12]. The drug is considered to undergo the hepatic metabolism pathway and its use in treatment should be monitored due to possible hepatotoxic impact [13,14]. As molindone has been introduced anew to market and is used in schizophrenia therapy, the issue of the hepatotoxicity origin is still not better known
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