Pharmacokinetic-pharmacodynamic modeling analysis for hydroxysafflor yellow A-calycosin in compatibility in normal and cerebral ischemic rats: A comparative study

Abstract

Objective: Astragalus and Safflower are commonly used in the treatment of stroke. Studies have shown that their two active components, hydroxysafflor yellow A (HSYA) and calycosin (CA), have protective effects on cerebral ischemia-reperfusion injury (I/R). However, the pharmacokinetic-pharmacodynamic (PK-PD) modeling study of the combination of the two components has not been reported in rats. The study aimed to perform combined PK-PD modeling of HSYA and CA in normal and cerebral ischemia model rats to explain quantitatively their time-concentration-effect relationship.

Methods: To make the middle cerebral artery occlusion (MCAO) model. SD rats were randomly divided into normal treated group (NTG) (n = 6), model group (MDG) (n = 6) and model treated group (MTG) (n = 6). Plasma was collected from the mandibular vein after 0, 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 180, and 240 min after intravenous administration. Rats in NTG and MTG were administered the same dose of HSYA (5 mg/kg) and CA (8 mg/kg) by tail vein injection. HPLC-VWD method was used for detection and analysis. Simultaneously, ELISA was performed to detect the levels of IL-1β and caspase-9 in rat plasma at different time points. The improvement in the above indicators was compared after administration. Lastly, after combining the pharmacokinetic parameters and pharmacodynamic indicators in vivo, DAS 3.2.6 software was used to fit the PK-PD model.

Results: The MCAO model was successfully established. Compared to NTG, there was a significant difference (P < 0.05) in t_1/2α, t_1/2β, V₁, V₂, CL₁, CL₂, AUC_(0-t), AUC _(0-∞), and K₁₂ of MTG for HSYA, and there was a significant difference (P < 0.05) in t_1/2α, V₁, CL₁, AUC_(0-t), AUC _(0-∞), and K₁₀ of MTG for CA_. Compared to NTG, the PK parameters of t_1/2α, V₁, V₂, CL₁, and K₁₀ were higher for HSYA in MTG, while AUC_(0-t), AUC _(0-∞), K₁₂, and K₂₁ were lower; the PK parameters of t_1/2α, V₁, V₂, AUC_(0-t), and AUC_(0-∞) were higher for CA in MTG, while CL₁, CL₂, K₁₀, K₁₂, and K₂₁ were lower. Also, the results of PD showed extremely significant differences in the levels of caspase-9 and IL-1β at the different time points in MTG (P < 0.01) compared with 0 min. The levels of caspase-9 and IL-1β in NTG rats showed little fluctuation and were relatively stable; however, their levels in MTG showed a downward trend with time. There were highly significant differences in the levels of each of the pharmacodynamic indicators at every time point between NTG and MTG (P < 0.01).

Conclusion: The PK-PD model of the combined administration of HSYA and CA was successfully established in rats, and the differences in pharmacodynamic and pharmacokinetic properties between the normal and cerebral ischemic rats were evaluated. Based on comprehensive data analysis, we found that the combination of HSYA and CA may exert protective effects against I/R injury in rats via anti-apoptotic and anti-inflammatory pathways. The study provided additional insights into the development of drugs for ischemic stroke as well as the design of appropriate dosing regimens.

Keywords: Calycosin; Cerebral ischemia; Hydroxysafflor yellow A; PK-PD; Pharmacodynamics; Pharmacokinetics.