基于"君臣配伍"探讨芍药甘草汤通过激活PXR途径影响紫杉醇药动学的机制研究

Shaoyao-Gancao-Tang (SGT) is administered in combination with paclitaxel to prevent the pain induced by chemotherapy. But until now, it has not been clari?ed whether there are any pharmacokinetic interactions between SGT and paclitaxel. Our preliminary research revealed that pharmacokinetic parameters of paclitaxel were significantly altered with SGT. Compatibility of Radix paeoniae alba and Radix Glycyrrhizae influenced effective compounds' pharmacokinetics. Data show that extract of Radix Glycyrrhizae can activate the nuclear receptor PXR and then induce expression of drug metabolism enzyme and drug transporter protein. The variance of the CYP3A4 and P-gp activity is the plausible explanation for the changed blood concentration of paclitaxel. So, we hypothesize that the signal pathway of SGT-PXR-CYP3A4/MDRl may result in the interaction between SGT and paclitaxel, and compatibility of Radix paeoniae alba and Radix Glycyrrhizae has a synergism effect in the process. The present study will observe the effect of SGT and its single herb decoction on the pharmacokinetics of paclitaxel, aim to approach the mechanism and explore the role of compatibility of Chinese compound medicine by techniques such as UPLC，double fluorescent reporter genes platform，plasmid transfection，RT-PCR. The results would be helpful to apply a theoretical basis for combination of Chinese traditional and western medicine treatment of tumors of the rational use of drugs from a new viewpoint.

芍药甘草汤与紫杉醇合用以预防化疗后疼痛的副反应。但是，芍药甘草汤对紫杉醇的药动学影响的研究，迄今国内外尚无报道。我们的前期研究发现芍药甘草汤导致紫杉醇的药动学显著变化；白芍和甘草配伍影响其效应成分的药动学。文献表明，甘草提取物能够激活核受体PXR，从而诱导药物代谢酶以及药物转运体蛋白的表达；CYP3A4以及P-糖蛋白的功能改变是导致紫杉醇血药浓度发生变化的主要原因之一。因此，我们推测芍药甘草汤对紫杉醇药动学的影响可能是通过芍药甘草汤-PXR-CYP3A4/MDRl途径介导，而方中白芍和甘草配伍对这一过程起协同作用。本项目应用UPLC、双荧光报告基因平台、质粒转染和RT-PCR等技术，从体内和体外两个层次，观察芍药甘草汤及其拆方对紫杉醇药动学的影响并研究其作用机制，探讨中药复方配伍在这一过程中的作用。本课题将从新的视角为中西药结合治疗肿瘤的合理用药提供理论依据。

肿瘤患者化疗前能否服用中药，存在很大争议。本项目从药物代谢的角度对该问题进行了探索研究。结果显示，芍药甘草汤及甘草影响化疗药物紫杉醇的代谢。我们建议化疗前不使用中药，化疗结束后再进行中药调理治疗，提出化疗-中药的序贯疗法。本课题分别以高效液相色谱（HPLC）和液相色谱-质谱联用（LC-MS）为技术平台，对大鼠血浆中紫杉醇的分析方法进行了研究。建立了灵敏度高、特异性好的定量分析方法，并进行了方法验证。实验结果显示，芍药甘草汤及甘草单煎液多次给药导致紫杉醇的药动学显著改变。本课题建立体外的细胞平台，在双荧光报告基因和mRNA水平层面探讨芍药甘草汤及其拆方对CYP3A4以及P-糖蛋白转录水平的影响。结果显示：芍药甘草汤通过PXR信号通路诱导CYP3A4以及MDR1的表达，从而影响紫杉醇的代谢。通过比较芍药甘草汤全方及拆方的干预效果，结果显示从药物代谢的角度阐明芍药甘草汤中白芍和甘草的配伍机制，并揭示配伍对中药-化疗药物相互作用的过程中的作用。另外，我们加做了白芍和甘草主要成分单体及单体组合的干预效果。结果显示，甘草和白芍及其主要活性成分（甘草次酸和芍药苷）有配伍协同作用。