晚期氧化蛋白终产物影响慢性肾脏病大鼠模型中芦荟大黄素、大黄素、大黄素和大黄酚的药代动力学
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南方医科大学深圳医院药剂科,深圳,518100,广东,中国

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Advanced Oxidation Protein Products Regulate the Pharmacokinetics of Aloe-emodin, Emodin, Rhein, and Chrysophanol in Chronic Kidney Disease Rats
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Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, Guangdong, China

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    摘要:

    背景: 晚期氧化蛋白终产物(AOPPs)是慢性肾脏病(CKD)进展的产物及加速器,它影响肝脏的功能。复方黄甘颗粒(HGGs)常用于预防CKD的进展,但其主要成分芦荟大黄素、大黄素、大黄酸和大黄酚在CKD状态下的HGGs中的药代动力学尚不清楚。目标: 探讨AOPPs对芦荟大黄素、大黄素、大黄酸和大黄酚体内药代动力学的影响及其分子机制。方法: 我们构建5/6肾切除术(5/6 nx)、腺嘌呤诱导和AOPP腹腔注射的大鼠模型。口服HGGs后,采用高效液相色谱(HPLC)检测血浆样品中芦荟大黄素、大黄素、大黄酸和大黄酚的浓度,用PKSolver软件分析其药代动力学参数。采用酶联免疫吸附法(ELISA)检测血浆中IL-6和TNF-α的浓度。在HepG2细胞中进行RT-PCR,探讨TNF-α和IL-6对CYP1A2和CYP3A4 mRNA表达的影响。结果: 建立的HPLC方法适用于血浆样品中4种蒽醌类化合物的定量,线性关系(R2 > 0.9931)、精密度(< 9.4%)和准确度(±10%)。在5/6 nx、腺嘌呤和AOPPs处理的大鼠中,TNF-α和IL-6的浓度显著升高。在5/6 nx和腺嘌呤大鼠中,芦荟大黄素、大黄素、大黄酸和大黄酚的药代动力学参数(t1/2、MRT0-∞和AUC0-∞)显著升高。在AOPPs处理的大鼠中,AOPPs浓度显著升高,4种蒽醌的药代动力学参数也明显改变。结论: 炎症因子的产生可能是AOPPs调节CKD大鼠中芦荟大黄素、大黄素、大黄酸和大黄酚的药代动力学的重要原因之一。芦荟大黄素、大黄素、大黄酸和大黄酚在CKD中的研究有助于临床中HGGs临床合理应用。

    Abstract:

    Background As accelerators and products of the progression of chronic kidney disease (CKD), advanced oxidation protein products (AOPPs) affect the function of the liver. Huang Gan granules (HGGs) are commonly used to prevent the progression of CKD, but the pharmacokinetics of aloe-emodin, emodin, rhein, and chrysophanol in HGGs in CKD remain unknown. Objective To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin, emodin, rhein, and chrysophanol in HGGs. Methods We constructed 5/6 nephrectomised (5/6 nx), adenine-induced (adenine) and AOPP-treated rat models. After oral administration of HGG, the concentrations of aloe-emodin, emodin, rhein, and chrysophanol in the plasma samples were detected by high-performance liquid chromatography (HPLC), and their pharmacokinetics were analysed with the PKSolver software. The plasma concentrations of IL-6 and TNF-α are detected by enzyme linked immunosorbent assay (ELISA). The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-α and IL-6 on the mRNA expression of CYP1A2 and CYP3A4. Result The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear (R2 > 0.9931), precision (< 9.4%) and accuracy (±?10%). In 5/6 nx, adenine and AOPPs-treated rats, the concentrations of TNF-α and IL-6 were increased. In 5/6 nx and adenine rats, the pharmacokinetic parameters (t1/2, MRT0-∞ and AUC0-∞) of aloe-emodin, emodin, rhein, and chrysophanol were, respectively, significantly increased and correlated with the concentration of AOPPs. In AOPPs-treated rats, the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased. Conclusion In summary, inflammatory cytokine production may be one of the important causes in AOPPs' regulating the pharmacokinetic of aloe-emodin, emodin, rhein, and chrysophanol in the CKD rats. Studies of aloe-emodin, emodin, rhein, and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.

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  • 在线发布日期: 2023-11-24
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