Pharmacokinetic-Pharmacodynamic Modeling of Active Components from Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) in Focal Cerebral Ischemia Rats

• Published in: Revista brasileira de farmacognosia Vol. 32; no. 4; pp. 544 - 554
• Main Authors: Zhou, Huifen, Hu, Mingxu, Yang, Yuting, Lin, Bingying, Ai, Jinchao, Yang, Jiehong, He, Yu, Wan, Haitong
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2022
• Subjects: Medicine; Original Article; Pharmacy; Pharmacodynamics; Ischemic stroke; Pharmacokinetics-pharmacodynamics model; Pharmacokinetics; Anti-inflammatory
• ISSN: 1981-528X; 1981-528X
• DOI: 10.1007/s43450-022-00265-7

This study investigated the pharmacokinetics and pharmacodynamics of the main active components of Danshen and Honghua and their time-concentration-effect relationship. A preparation containing active components (danshensu, protocatechuic aldehyde, salvianolic acid B, and hydroxy safflor yellow A) were administrated to rats after middle cerebral artery occlusion for 1 h followed by reperfusion. The method for determining the concentrations of the main active components in rat plasma was established by high-performance liquid chromatography. At the same time, the anti-inflammatory effect of corresponding pharmacokinetic time points was detected by an enzyme-linked immunoassay kit. The pharmacokinetics results showed that danshensu and hydroxy safflor yellow A were fitted with the three-compartment model, and protocatechuic acid, vanillic acid, and salvianolic acid B were fitted with the two-compartment model. In the plasma of model rats, the expression of tumor necrosis factor-alpha (TNF-α) and IL-1β significantly increased with time, indicating that cerebral ischemia-reperfusion injury is closely related to inflammatory reactions. Compared with the model group, the levels of TNF-α and IL-1β in the plasma of rats after administration were significantly decreased. Drug and statistics 3.2.6 software was used to fit the pharmacokinetics-pharmacodynamics binding model of the intensity effect of each component on anti-TNF-α and anti-IL-1β, and the pharmacokinetics-pharmacodynamics model fitted the sigmoid E max model. There was a good correlation between the fitted results and the measured data ( p < 0.05), which could be used to predict the variation in drug concentration and effect with time. This study developed a pharmacokinetics-pharmacodynamics model to assess time-concentration-effect relationships for the anti-inflammatory effects of the main active components of Danshen and Honghua and provides a better understanding of the mechanisms of action and combination of Danshen and Honghua for the treatment of ischemic strokes. It also provides important clinical data on reliable pharmacokinetics and pharmacodynamics and guides the rational use of drugs in clinical practice. Graphical abstract