RESUMO
In this paper, the integrated pharmacokinetics (PK) of an Acanthopanax senticosus extract preparation (ASEP, named as Ciwujia injection in clinic in China) was explored by combining with multi-component PK in rats, virtual screening, systems pharmacology and molecular docking. Firstly, the ingredients in ASEP with high contents and detectable property in rat plasma were selected. Next, the PK study of the resulted ingredients was performed in rats (1.76 ml/kg and 3.52 ml/kg of 5 times concentrated ASEP, single i.v.). Meanwhile, the drug targets for the ingredients screened out were predicted by using a target fishing online server, PharmMapper (http://www.lilab-ecust.cn/pharmmapper/) with a fit filtration threshold of z'-score >0. Next, the network pharmacology, molecular docking, diseases ontology (DO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed respectively for the predicted targets. Finally, the supporting evidences were obtained to characterize the PK markers and carry out the integrated PK study with "plasma-drug concentration sum" or "plasma-drug AUC weighted" methods. As a result, 6 ingredients, involving 5-caffeoylquinic acid (5-CQA), 3-CQA, 4-CQA, protocatechuic acid, eleutheroside B, and gentiopicroside were selected, and their PK profiles were elucidated. The 6 ingredients were highly related to arteriosclerotic cardiovascular disease and atherosclerosis and could mainly interact with similar targets, e.g., GSK3B, PDPK1, PLAU, etc., or pathways, e.g., Insulin, VEGF, FoxO, etc, providing the basis for integrating plasma drug concentration. Ultimately, the 6 ingredients were considered as PK markers and the whole in vivo process of ASEP were characterized. Our study would enhance understanding of the therapeutic effects and mechanisms of ASEP against cardiovascular diseases, and provided useful insights for future integrated PK study on anti-cardiovascular diseases TCM injections.
RESUMO
This paper reported a feasibility study strategy of identifying pharmacokinetic (PK) markers for a cardiovascular herbal medicine, Guanxin Danshen drop pill (GDDP). First, quantification analysis revealed the constituent composition in the preparation by high-performance liquid chromatography (HPLC). Subsequently, physiochemical property calculation predicted the solubility and intestinal permeability of the constituents in the preparation. Furthermore, HPLC-MS analysis ascertained the absorbable ingredients and their PK properties in rat plasma. The main effective substances from the ingredients absorbed into blood and their cardiovascular effects were also predicted by systems pharmacology study, and were further confirmed by in vivo protective effects on isoprenaline-induced myocardial injury in mice. Finally, the ingredients with high content, representative structure feature, favorable PK properties, high relevant degree to myocardial ischemia (MI) issues, and validated therapeutic effects were considered as the PK markers for the preparation. Ginsenosides Rg1, Rb1, and tanshinone (TS) IIA were identified originally as PK markers for representing PK properties of GDDP. In addition, integrated PK studies were carried out according to previous reports, viz. drug concentration sum method and the AUC weighting method, to understand the in vivo process of GDDP comprehensively. The present study maybe provide a reference approach to identify PK markers for cardiovascular herbal medicines.
