Comparative pharmacokinetics and hippocampal distribution of six major bioactive alkaloids in normal and Alzheimer’s disease rats after oral administration of Menispermi Rhizoma extract

Menispermi Rhizoma (MR), officially listed in the Chinese Pharmacopoeia, contains abundant and diverse alkaloids with significant therapeutic effects against Alzheimer’s disease (AD). However, the pharmacokinetic characteristics and hippocampal distribution of its major bioactive alkaloids in rats under different physiopathological conditions remain unclear. In this study, a systematic qualitative analysis of alkaloids in plasma and brain tissue of AD rats following oral administration of MR extract was performed by ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Subsequently, a sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to compare the pharmacokinetics and hippocampal distribution of six bioactive alkaloids (dauricine, daurisoline, dauricicoline, acutumidine, dauricoside, and 6- O -demethylmenisporphine) in sham-operated and AD rats. A total of 24 prototype alkaloids in the plasma and brain tissue of AD rats were identified. Pharmacokinetic analysis revealed that the C max , the area under the plasma concentration–time curve to the last measurable plasma concentration (AUC 0-t ), and the area under the plasma concentration–time curve to time infinity (AUC 0-∞ ) of acutumidine and 6- O -demethylmenisporphine were obviously increased in AD rats compared to sham-operated rats. Similar trends were observed for dauricine and dauricoside, suggesting enhanced absorption and delayed elimination. These changes may be attributed to the inhibition of drug-metabolizing enzymes and transporters in the gastrointestinal tract and liver or the reduced renal clearance under pathological states. Furthermore, all six alkaloids successfully crossed the blood-brain barrier and accumulated in the hippocampus. Notably, hippocampal drug concentrations were higher in sham-operated rats than in AD rats, likely reflecting the degeneration and cellular damage of hippocampal neurons in the disease state. These findings lay a robust foundation for elucidating the pharmacodynamic material basis of MR in treating AD.