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Evodiamine is an indoloquinazoline alkaloid isolated from the fruit of Evodia rutaecarpa, which has a wide range of pharmacological effects like anti-tumor and anti-inflammatory effects. This study was intended to investigate the metabolic characteristics of evodiamine in human liver microsomes and hepatocytes by ultra-high performance liquid chromatography coupled with a Q Exactive mass spectrometer. A total of 12 phase I metabolites were detected in human liver microsomes; whereas in human hepatocytes 19 metabolites, including seven phase II metabolites were detected. The structures of the metabolites were characterized based on their accurate masses, fragment ions, and chromatographic retention times. Four metabolites (M1, M2, M5, and M7) were further unambiguously confirmed by matching their retention times, accurate masses, and fragment ions with those of their reference standards. Among these metabolites, 12 metabolites are first identified (M2, M5–M8, M10–M13, and M17–M19). The current study revealed that oxygenation, N-demethylation, dehydrogenation, glucuronidation, and GSH conjugation were the major metabolic pathways for evodiamine. This study elucidated the detailed metabolite profiles of evodiamine, which is helpful in predicting in vivo metabolism of evodiamine in human and in understanding the elimination mechanism of evodiamine and in turn, the effectiveness and toxicity.

Garcinia mangostana L. (mangosteen) is a famous tropical fruit that contains a large number of xanthones. Regular consumption of mangosteen may confer health benefits and prevent some diseases, such as malaria. Quinone reductase 2 (QR-2) is a cytosolic enzyme found in human red blood cells, and it is becoming a target for chemoprevention because it is involved in the mechanisms of several diseases, including malaria. To understand whether the xanthones present in mangosteen might inhibit the activity of QR-2, blood samples were collected from rat following the oral administration of mangosteen extract and then incubated with QR-2 followed by UF–HPLC–QTOF/MS analysis to rapidly screen for and identify the QR-2-inhibiting xanthones. A total of 16 xanthones were identified, and six of these (α-mangostin, γ-mangostin, 8-deoxyartanin, 1,3,7-trihydroxy-2,8-di­(3-methylbut-2-enyl)­xanthone, garcinone E, and 9-hydroxycalabaxanthone) were subjected to QR-2 inhibition assay. γ-Mangostin exhibited the strongest inhibition, achieving an IC50 value of 3.82 ± 0.51 μM. Its interaction with QR-2 was found to involve hydrogen bond and arene–arene interaction as revealed by molecular docking. The present study could provide new insight into the potential application of mangosteen as functional food ingredients for inhibiting the activity of QR-2. However, the extent of daily intake of mangosteen required and the exact contribution of mangosteen to the prevention and treatment of malaria remain subjects of further study.

Tirabrutinib is an orally administered Bruton's tyrosine kinase (BTK) inhibitor developed for the treatment of autoimmune disorders and haematological malignancies. The goals of this study were to identify the metabolites of tirabrutinib and to propose the metabolic pathways.Methods: Tirabrutinib was individually incubated with rat, dog and human liver microsomes at 37 C for 1 h. To trap the potential reactive metabolites, glutathione (GSH) was incorporated into the incubation samples. The incubation samples were analysed using ultra-high-performance liquid chromatography combined with highresolution mass spectrometry (UHPLC-HRMS). The metabolites were identified and characterized by exact masses, product ions and retention times.Results: A total of 18 metabolites, including four GSH conjugates, were identified and characterized in terms of elemental compositions and product ions. The

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