ABSTRACT
The herb-pair Gingseng-Fuzi (the root of Aconitum carmichaelii ) is named as Shenfu prescriptions and is popular in traditional Chinese medicine for treatment of heart failure, and even shock with severe-stage COVID-19. However, a narrow therapeutic window of Fuzi may cause significant regional loss of property and life in clinics. Therefore, systemic elucidation of compatibility mechanism using in vivo comparative exposure is particularly crucial to improve the safety dose window of Shenfu prescriptions. A high performance liquid chromatography-mass spectrometry method was developed for quantification of 11 aconitines in SD rat plasma within 9 min, and a systemic comparison with their pharmacokinetic characteristics after oral administration of a safe dosage of 2 g/Kg of Fuzi and Ginseng-Fuzi decoction for 24 h was conducted. Nine representative diester, monoester, and non-ester aconitines and two new active components ( e . g . songorine and indaconitine) were all adopted to elucidation of the differences of the contents in decoction and the pharmacokinetic parameters in vivo , including the terminal elimination half-life (T1/2), area under the concentration-time curve, mean residence time, time to achieve maximum concentration (Cmax), and maximum plasma concentration. It was found that the compatibility with Fuzi and gingseng could significantly increase their bioavailability of active components. Moreover, the in vivo exposure and the T1/2 of diester aconitines (aconitine and mesaconitine) and the monoester aconitines (benzoylaconitine, benzoylmesaconitine, and benzoylhypaconitine) were all increased significantly, indicating the efficacy was increased simultaneously. Songorine shown the largest Cmax with a potential decardiotoxicity ability. This study provided a solid pharmacokinetic parameters for development of safe and effective new Shenfu oral prescriptions.