A strategy for herbal interaction between Ziziphi spinosae Semen and vinegar processed Schisandrae Chinensis fruit when co-decocted based on process route design of new drug of Chinese herbal formulae

For characterizing the influence of vinegar processed Schisandrae Chinensis Fruit (vSCF) on the dissolution of constituents of Ziziphi spinosae Semen (ZSS) when co-decocted, a strategy for herbal interaction was currently proposed based on process route design of new drug of Chinese herbal formulae. Firstly, the content of jujuboside A (JuA) in ZSS-vSCF co-decoction was determined at different ratios by high performance liquid chromatography coupled with evaporative light-scattering detector (HPLC-ELSD), to demonstrate the influence of vSCF on JuA of ZSS. As the results showed, the content of JuA was declined drastically in ZSS-vSCF co-decoction compared to the ZSS single decoction, especially at the ratio of 1:1. Hence, the ratio of 1:1 was used in the following studies. Furtherly, as pre-extraction is usually taken in the pharmaceutical industry of Chinese patent medicines (CPM) to avoid herbal interaction, thus the pre-extracted solvents of vSCF were investigated. The content of JuA in coupled decoction was indeed improved when vSCF was pre-extracted before co-decocted with ZSS. Among the pre-extracted solvents, 60% ethanol possessed a better-improved effect. Therefore, 60% ethanol extract of vSCF was treated with JuA and the transformed compounds of JuA can be identified by ultra high performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS). Then, we reported that jujubosides, the main saponins in ZSS, would be transformed into its ebelin-lactone forms through dehydration, RDA cleavage and hydrolysis of glycosidic bond, which could be induced by organic acid in vSCF. Additionally, to elucidate the comprehensive influence, 45 compounds were tentatively identified by UPLC–ESI-Q-TOF-MS/MS, and their dissolution variation in different ZSS-vSCF co-decoction was represented by manually acquired EICs, as well. It can be found that vSCF can promote extraction efficiencies of alkaloids and flavonoid O-glycosides of ZSS when co-decocted, while saponins were suppressed. Similarly, the pre-extraction of vSCF could reverse the suppression. To further elucidate the significance of ZSS-vSCF co-decoction, a comparison of molecular modeling between JuA and its ebelin-lactone form were carried out, revealing that the corresponding ebelin-lactone form had a stronger binding affinity than JuA toward calmodulin (CaM). Collectively, to lower the herbal interaction, a pre-extraction method was developed against the decrease of JuA in ZSS-vSCF co-decoction. And the dissolution of different types of constituents in ZSS was investigated by a semi-quantitative method, as well. Also, ebelin-lactone form of JuA, which resulted from ZSS-vSCF co-decoction, demonstrated a stronger binding affinity toward CaM in virtual screening, but the future pharmacological and pharmacokinetic research is worthy to be further studied.