Abstract
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.
Highlights
Acanthopanax senticosus (Rupr. et Maxim) Harms, called Ciwujia in China, belonging to the family of Araliaceae, is a hardy shrub, native to the northeastern region of China, Korea, and Japan, and the far-eastern region of Russia (Huang et al, 2011)
Beyond 5 min, only the 6 ingredients, including 5-caffeoylquinic acid (5-CQA), 3-CQA, 4-CQA, PCA, EB, and GPS possessed the detectable property in rat plasma, suggesting their favorable PK properties possibly due to their high contents in the preparation
An integrated PK of ASEP in rats was explored by combination of multi-component PK, systems pharmacology and bioinformatics analysis
Summary
Acanthopanax senticosus (Rupr. et Maxim) Harms, called Ciwujia in China, belonging to the family of Araliaceae, is a hardy shrub, native to the northeastern region of China, Korea, and Japan, and the far-eastern region of Russia (Huang et al, 2011). Et Maxim) Harms, called Ciwujia in China, belonging to the family of Araliaceae, is a hardy shrub, native to the northeastern region of China, Korea, and Japan, and the far-eastern region of Russia (Huang et al, 2011). This shrub has been utilized for the treatment of various ailments such as cancer (Huang et al, 2005), cardiovascular diseases (CVDs) (Li, 2003), cerebrovascular diseases (Li et al, 2009), neurodegenerative diseases (Shi and Chen, 2017), diabetes (Yu et al, 2016), and so on. Formulating the rational dosage regimens through understanding the in vivo pharmacokinetics (PK) of TCM injections is of great significance
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