Metabolic profile analysis of key pentacyclic triterpenoid saponins from Abrus cantoniensis Hance and the interaction with hepatoprotective pharmacodynamic targets.

This study aims to elucidate the "component-metabolism-activity" correlation of key pentacyclic triterpene saponins (soyasaponin I and kaikasaponin III) derived from Abrus cantoniensis. A sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was strictly validated for their simultaneous determination in Sprague-Dawley rat plasma following the oral administration of an Abrus cantoniensis extract (2 g/kg). Pharmacokinetic profiling revealed that kaikasaponin III exhibited higher systemic exposure and a longer mean residence time compared to soyasaponin I, though both demonstrated generally low systemic exposure. To explore their metabolic fate, in vitro Phase I metabolic stability and metabolite identification were conducted using a rat liver microsome system coupled with ultra-performance liquid chromatography-quadrupole-Exactive Orbitrap-mass spectrometry (UPLC-Q-Exactive Orbitrap-MS). Assays confirmed both saponins undergo extensive Phase I metabolism, primarily via oxidation, desaturation, and deglycosylation, with kaikasaponin III displaying a higher intrinsic clearance. Subsequently, molecular docking evaluated the binding affinities of the identified metabolites with key hepatoprotective targets, including BCL2L1, CASP3, MAPK8, MAPK14, NOS2, and PTGS2. Predictions indicated that the Phase I metabolites retained or even exhibited enhanced binding affinities-most notably toward MAPK14-compared to their parent compounds. This integrated approach reveals that the pharmacological efficacy of Abrus cantoniensis may be driven largely by its active metabolite clusters, providing a more nuanced framework for understanding the multi-component basis of this traditional medicine.