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Rationale Metabolite profiling is an integral part of the drug development process for selecting candidates with high therapeutic efficacy and low risk. Baricitinib (BARI) was approved in 2018 by the US Food and Drug Administration to treat rheumatoid arthritis. According to the available literature, no systematic study has been reported on the metabolite profiling of BARI. The biotransformation pathway of the drug has also not been established until recently. This study aims to identify BARI metabolites generated in in vitro matrices. Methods The in vitro metabolism study was carried out using rat liver microsome, human liver microsomes, and human S9 fraction. Ultra high‐performance liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry (U‐HPLC‐Q/TOF) and ultra‐high‐performance liquid chromatography/linear ion trap‐Orbitrap mass spectrometry (U‐HPLC/LTQ‐Orbitrap‐MS/MS) were used to identify and characterize the metabolites of BARI. The in silico toxicity of BARI and its metabolite was studied using ProTox‐II toxicity predictor software. Results A total of five new metabolites have been identified amongst which two (M1 and M2) were detected on both U‐HPLC/LTQ‐Orbitrap‐MS/MS and U‐HPLC‐Q/TOF and two additional metabolites (M4 and M5) were detected on U‐HPLC/LTQ‐Orbitrap‐MS/MS. Moreover, one metabolite (M3) was only detected on LC‐QTOF. Conclusions The major metabolic changes were found to be N‐dealkylation, demethylation, hydroxylation, and hydrolysis. Metabolites M3 and M4 were found to have the potential for carcinogenicity. The novelty of the study can be justified by the unavailability of any previous research on in vitro metabolite profiling of BARI. Furthermore, this is the first time the biotransformation pathway of BARI and the toxicity potential of its metabolites have been reported.

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