Rapid Characterization of the Potential Active of Sinomenine in Rats by Ultra‐High‐Performance Liquid Chromatography‐Quadrupole‐Exactive Orbitrap Mass Spectrometry and Molecular Docking

Abstract

Sinomenium acutum (Thunb.) Rehd. et Wils is widely used in the treatment of rheumatoid arthritis, with its alkaloid compound sinomenine (SIN) being renowned for its significant anti‐inflammatory properties. However, despite its widespread application, the in vivo anti‐inflammatory mechanisms and metabolic pathways of SIN remain incompletely understood. This study established a rapid and reliable method based on an ultra‐high‐performance liquid chromatography method coupled with Quadrupole‐Exactive Orbitrap mass spectrometry and molecular docking to identify and characterize SIN and 69 metabolites in rat plasma, urine, and feces, revealing primary metabolic pathways of hydroxylation, demethylation, sulfation, and glucuronidation. Molecular docking results revealed that phase I reactions, including dedimethylation, demethylation, dehydrogenation, and dihydroxylation, along with their composite reactions, were pivotal in influencing SIN's in vivo anti‐inflammatory activity. M28, M36, and M59 are potentially the most anti‐inflammatory active metabolites of SIN in vivo. This comprehensive analysis unveils SIN's metabolic pathways, offering insights into its biological processes and suggesting a novel approach for exploring active drug constituents. These findings pave the way for further understanding SIN's anti‐inflammatory mechanisms, contributing significantly to the development of new therapeutic strategies.