Analysis of compatibility mechanism of shenxiong glucose injection after multiple dosing based on differences of PK-PD correlation and cytochrome P450 enzyme

Abstract

Shenxiong glucose injection (SGI) containing a water extract from the roots of Danshen and Ligustrazine hydrochloride, is the main drug used for the prevention and treatment of acute myocardial ischemia (AMI) in China. Based on the characteristics of drug clinical applications, this study aims to uncover the compatibility mechanism of SGI by investigating pharmacokinetic (PK) and pharmacodynamic (PD) differences between Danshen glucose injection (DGI), Ligustrazine glucose injection (LGI) and SGI groups after multiple dosing during the pathological state from the perspective of metabolic enzymes. Compared to the LGI group, the absorption (C_max) and exposure (AUC) of ligustrazine increased significantly, and the protein expression of CYP1A2, CYP2C11 and CYP3A2 in the SGI group decreased significantly. Furthermore, the PK and PD experimental data for Danshen and ligustrazine in AMI rats were fitted to obtain a PK-PD binding model with three components. PK-PD parameter analysis showed that in the SGI group the IC50 values of ligustrazine and danshensu on AST, CK-MB, cTn-I and the IC₅₀ values of rosmarinic acid on AST and CK-MB were lower than the DGI or LGI group. It is speculated that Danshen inhibited CYP1A2, CYP2C11 and CYP3A2 mediating the metabolism of ligustrazine and decreased the expression of these three isozymes, which further affected the in vivo process of ligustrazine. Moreover, the combination of Danshen and ligustrazine could have better regulating effect on AST, CK-MB and cTn-I. This preliminary study has provided a scientific basis for understanding the compatibility mechanism of SGI from the viewpoint of the regulation of CYP enzymes in the PK-PD model.

Keywords: CYP enzymes; Compatibility; Danshen; Ligustrazine hydrochloride; PK-PD correlation.