Identification of Pharmacokinetic Markers for Guanxin Danshen Drop Pills in Rats by Combination of Pharmacokinetics, Systems Pharmacology, and Pharmacodynamic Assays

Abstract

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.

Tanshinones, Critical Pharmacological Components in Salvia miltiorrhiza

“…Cardiovascular diseases refer to ischemic or hemorrhagic diseases in the heart, brain and whole body tissues caused by hyperlipidemia, blood viscous, atherosclerosis, and hypertension. S. miltiorrhiza and its compound preparations, such as composite Danshen droplet pills ( Zhang et al, 2008 ) and Guanxin Danshen drop pills ( Yao et al, 2018 ), have achieved good curative effects in the clinical treatment of cardiovascular diseases. Modern pharmacological research has found that S. miltiorrhiza has been widely used in the treatment of coronary artery, myocardial ischemia and myocardial infarction, improvement of microcirculation, and reduction of myocardial oxygen consumption.…”

An Integrated Pharmacokinetic Study of an Acanthopanax senticosus Extract Preparation by Combination of Virtual Screening, Systems Pharmacology, and Multi-Component Pharmacokinetics in Rats

“…Accordingly, considering all these factors, the six main ingredients, 4-CQA, GPS, 5-CQA, PCA, EB, and 3-CQA should be selected as drug markers to profile the in vivo behavior of ASEP. All these provide supportings to characterize the whole in vivo process of ASEP by integrating the plasma drug concentration of these ingredients using simple methods, like "plasma drug concentration sum method" and the "AUC weighting integrated method" (Yao et al, 2017;Shi et al, 2018;Yao et al, 2018;Huang et al, 2019). Therefore, we next calculated the total concentrations of the markers in rat plasma according to the previous reports.…”

“…It is based on the multi-components PK, as well as takes into account the pharmacological effects and the contribution weights of the multi-components to the treatment effects. Thus, the integrated PK parameters could be helpful for the dosage regimen design of complex TCMs' preparations (Yao et al, 2017;Shi et al, 2018;Yao et al, 2018;Huang et al, 2019). In the evaluation of efficacy, besides in vivo and in vitro experiments, systems pharmacology has received more and more attention due to its serviceability on predicting the therapeutic effects and mechanisms of multiple ingredients in TCMs (Fu et al, 2014;Liu et al, 2016;Zhang et al, 2016).…”

“…In the evaluation of efficacy, besides in vivo and in vitro experiments, systems pharmacology has received more and more attention due to its serviceability on predicting the therapeutic effects and mechanisms of multiple ingredients in TCMs (Fu et al, 2014;Liu et al, 2016;Zhang et al, 2016). Furthermore, systems pharmacology has been considered in predicting the main effect substances and identifying pharmacokinetic markers for a TCM, which was helpful to the integrated PK study of the TCM (Yao et al, 2018). Up to date, the systems pharmacology study on ASEP against CVDs has not been reported.…”

Dissection of effect mechanisms of Kudiezi injection against myocardial ischemia based on virtual screening and systems pharmacology approach

“…In the recent years, owing to the convenient and powerful properties on exploring the inner relationship among multiple ingredients, multiple targets and multiple pathways for a complex drug system, systems pharmacology study has become a popular trend on dissecting the action mechanism of compound formula, e.g. traditional Chinese medicines, herbal medicines or their preparation products [14][15][16][17][18][19]. Also, systems pharmacology was considered to be able to provide valuable clues on identifying the active ingredients from complex herbal formula [17][18][19].…”