丹红注射液心血管保护成分的药代动力学-药效学研究。
A pharmacokinetic-pharmacodynamic study to elucidate the cardiovascular protective constituents in Danhong Injection.
机构信息
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China; Peking University-Yunnan Baiyao International Medical Research Center, 38 Xueyuan Road, Beijing 100191, China.
出版信息
J Pharm Biomed Anal. 2022 Sep 20;219:114953. doi: 10.1016/j.jpba.2022.114953. Epub 2022 Jul 20.
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.
丹红注射液（DHI）是治疗心血管疾病最常用的中药制剂之一。然而，DHI 的有效成分尚未得到很好的阐明。在本研究中，首次采用药代动力学-药效学（PK-PD）方法来阐明 DHI 的有效化合物。首先，通过超声心动图和组织病理学研究，证明 DHI 对肾上腺素诱导的急性血瘀大鼠模型具有心血管保护作用。其次，通过 ELISA 检测血浆中 4 种血瘀相关细胞因子的水平。第三，采用 UHPLC-Q-Orbitrap-MS 测定 DHI 中 10 种化合物的血浆浓度。最后，建立 PK-PD 模型，描述 DHI 给药后 0-12 h 内化合物浓度与血浆细胞因子水平之间的关系。结果表明，DHI 可减轻心血管损伤，调节 IL-2、cTnT、VEGF 和 VEGFR-1。除内源性代谢物胞苷和尿苷外，丹参素、迷迭香酸和丹酚酸 B 表现出最高的血浆暴露。PK-PD 相关分析表明，丹酚酸 A、咖啡酸和阿魏酸的浓度与 cTnT 水平呈负相关，而丹酚酸 A 的浓度与 IL-2 水平呈负相关。这些化合物可能有助于 DHI 的心血管保护作用。
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