Sun Jinzhou, Chen Qianqian, Zhuang Chumeng, Li Xiaohong, Yu Li, Jin Weifeng
School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Sci Rep. 2025 May 5;15(1):15631. doi: 10.1038/s41598-025-00182-4.
Develop a novel coupled PK-PD model and apply it to quantitatively evaluate the synergistic effects of Hydroxysafflor Yellow A (HSYA) combined with Calycosin (CA) in the treatment of ischemic stroke. A total of 6 rats were modelled for middle cerebral artery occlusion (MCAO). Plasma was collected from the submandibular venous plexus of rats after the administration of HSYA and CA, and was detected and analyzed by LC-MS method. The plasma expression levels of Caspase-9, IL-1β and SOD in rats were also determined by ELISA kit. Meanwhile, a coupled PK-PD model was proposed, incorporating interaction terms between drugs and coupling of pharmacodynamic effects, to quantitatively reveal their interactions. Moreover, a numerical solution technique based on optimization methods was proposed, enabling the model to be effectively applied to experimental data. Based on the coupled PK model, HSYA and CA significantly increased each other's metabolic rates. The model also showed that CA had a larger apparent volume of distribution and clearance in rats, while HSYA had a shorter mean retention time and elimination half-life. The coupled PK-PD model indicated a synergistic effect between HSYA and CA on all three pharmacodynamic markers, with HSYA contributing more significantly. Despite individual variability among the six rats, the parameter interpretations remained consistent. The proposed coupled PK-PD model and its numerical solution algorithm successfully revealed the synergistic effects of HSYA and CA in the treatment of ischemic stroke. This model lays the foundation for future models with more complex interactions and effects.
建立一种新型的药代动力学-药效学（PK-PD）耦合模型，并将其应用于定量评估羟基红花黄色素A（HSYA）联合毛蕊异黄酮（CA）治疗缺血性中风的协同作用。总共6只大鼠进行大脑中动脉闭塞（MCAO）建模。在给予HSYA和CA后，从大鼠下颌下静脉丛采集血浆，并采用液相色谱-质谱联用（LC-MS）法进行检测和分析。大鼠血浆中Caspase-9、白细胞介素-1β（IL-1β）和超氧化物歧化酶（SOD）的表达水平也通过酶联免疫吸附测定（ELISA）试剂盒进行测定。同时，提出了一种PK-PD耦合模型，纳入药物之间的相互作用项和药效学效应的耦合，以定量揭示它们之间的相互作用。此外，还提出了一种基于优化方法的数值求解技术，使该模型能够有效地应用于实验数据。基于耦合的PK模型，HSYA和CA显著提高了彼此的代谢率。该模型还表明，CA在大鼠体内具有更大的表观分布容积和清除率，而HSYA的平均保留时间和消除半衰期较短。PK-PD耦合模型表明HSYA和CA对所有三个药效学标志物均有协同作用，其中HSYA的作用更为显著。尽管6只大鼠之间存在个体差异，但参数解释保持一致。所提出的PK-PD耦合模型及其数值求解算法成功揭示了HSYA和CA治疗缺血性中风的协同作用。该模型为未来具有更复杂相互作用和效应的模型奠定了基础。
