A pharmacokinetic-pharmacodynamic study to elucidate the cardiovascular protective constituents in Danhong Injection

Danhong Injection (DHI) is one of the most popular Chinese medicine formulations to treat cardiovascular diseases. However, the effective components of DHI have not been well addressed. In the present study, a pharmacokinetics-pharmacodynamics (PK-PD) approach was employed to elucidate the effective compounds of DHI for the first time. Firstly, the cardiovascular protective effect of DHI was demonstrated on an adrenaline-induced acute blood stasis rat model by echocardiography and histopathology. Secondly, the levels of four blood stasis-related cytokines in plasma were examined by ELISA. Thirdly, the plasma concentrations of 10 compounds in DHI were determined using UHPLC-Q-Orbitrap-MS. Finally, PK-PD profiles were established to describe the relationship between compound concentrations and cytokine levels in plasma at 0-12 h following DHI administration. The results showed that DHI attenuated cardiovascular injury and regulated IL-2, cTnT, VEGF, and VEGFR-1. Except for the endogenous metabolites cytidine and uridine, danshensu, rosmarinic acid, and salvianolic acid B exhibited the highest plasma exposure. PK-PD correlation analysis indicated that concentrations of salvianolic acid A, caffeic acid, and ferulic acid were negatively correlated with the level of cTnT, while the concentration of salvianolic acid A was negatively correlated with the level of IL-2. These compounds may contribute to the cardiovascular protective effect of DHI.