Profiling and Identification of the Metabolites of Evodiamine in Rats using Ultra–Performance Liquid Chromatography with Linear Ion Trap Orbitrap Mass Spectrometer

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Purpose: To develop a highly sensitive and specific ultra-performance liquid chromatography with linear ion trap Orbitrap mass spectrometer (UPLC-LTQ-Orbitrap) method to profile and identify the metabolites of evodiamine in rats.Methods: First, blood samples were collected after oral administration of evodiamine to rats (50 mg/kg). Next, the plasma samples were pretreated using a solid-phase extraction (SPE) method. Finally, all the samples were analyzed by ultra-performance liquid chromatography LTQ-Orbitrap mass spectrometry (UPLC-LTQ- Orbitrap) coupled with electrospray ionization source (ESI) in negative mode.Results: A total of 7 metabolites (2 phase I and 4 phase II metabolites, including 4 new metabolites, viz, 10-hydroxyevodiamine sulfate, 10-hydroxyevodiamine sulfate, 10-hydroxyevodiamine glucuronide and 3-hydroxyevodiamine glucuronide) as well as the parent drug itself , were detected and identified based on accurate mass measurements, fragmentation patterns, and chromatographic retention times. The in vivo metabolic reactions of evodiamine in rats were hydroxylation, hydroxylation + sulfate conjugation, and hydroxylation + glucuronidation.Conclusion: These results provide better understanding of the metabolism of evodiamine as well as strong indications of the effective forms of the drug in vivo.Keywords: Evodiamine, Ultra–performance liquid chromatography with linear ion trap-Orbitrap, Hydroxyevodiamine sulfate, Hydroxyevodiamine glucuronide, Metabolites

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