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.
Background:
Ciwujia injection, prepared from water extraction of Acanthopanax senticosus,
is widely used for the treatment of cardiovascular diseases in the clinic in China. The ingredients of the
preparation are still not efficiently clear and its quality control method requires further improvement.
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Objective: In this paper, the qualitative and quantitative methods for quality control of Ciwujia injection
were originally developed by a combination of HPLC-Q-TOF-MS, HPLC-TQ-MS/MS and UPLCPDA.
Methods:
With HPLC-Q-TOF-MS and HPLC-TQ-MS/MS, compounds were identified firstly by comparison
of their MS spectra and retention times with those of standards or recorded information in the
literature. Further, a new UPLC-PDA method was originally established to simultaneously determine
the multiple ingredients in the preparations.
Results:
For qualitative analysis, 22 compounds were identified by the presented method. For quantitative
analysis, the validated method exhibited good linearity (R2 > 0.998), repeatability (RSD < 1.50%),
intra- and inter-day precisions (RSD < 8.33%) and recoveries (95.93-108.58%) for the simultaneous
determination of the active ingredients, including protocatechuic acid-3-glucoside, l-phenylalanine,
protocatechuic acid, neochlorogenic acid, chlorogenic acid, gentiopicroside, eleutheroside B, and cryptochlorogenic
acid, and was successfully utilized to analyze the eight compounds in 4 batches of Ciwujia
injection.
Conclusion:
The presented method is simple and rapid for quality control of Ciwujia injection, and
could provide a useful reference for the quality control and routine analysis of others Ciwujia preparations.
Safflower injection (SI), a water-extract preparation from safflower (Carthamus tinctorius L.), has been widely used for the treatment of cardio-cerebrovascular diseases. This work aims to develop an approach for identifying PK markers of cardiovascular herbal medicines using SI as a case study. Firstly, qualitative and quantitative analyses were performed to reveal ingredients of the preparation via HPLC-MS. Subsequently, multiple PK ingredients and integrated PK investigations were carried out to ascertain ingredients with favorable PK properties (e.g., easily detected at conventional PK time points and high system exposure) for the whole preparation. Next, ingredients against cardiovascular diseases (CVDs) in the preparation were predicted with target fishing and system pharmacology studies. Finally, ingredients with favorable PK properties, satisfactory PK representativeness for the preparation, and high relevance to CVDs were considered as potential PK markers. Their therapeutic effect was further evaluated using the H2O2-induced H9c2 cardiomyocyte-injured model and a proteomics study to identify objective PK markers. As results, it disclosed that SI mainly contains 11 ingredients. Among them, five ingredients, namely, hydroxysafflor yellow A (HSYA), syringin (SYR), p-coumaric acid (p-CA), scutellarin (SCU), and p-hydroxybenzaldehyde (p-HBA), showed favorable PK properties. HSYA, SYR, and rutin (RU) were predicted to show high relevance to CVDs and screened as potential PK markers. However, only HSYA and SYR were confirmed as therapeutic ingredients against CVDs. Combined with these findings, only HSYA demonstrated satisfactory representativeness on PK properties and therapeutic effects of multiple ingredients of the preparation, thereby indicating that HSYA is a potential PK marker for the SI. The results of this study can provide a reference for the characterization of PK markers for traditional Chinese medicines.
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