ETHNOPHARMACOLOGICAL RELEVANCE Rhein is a pharmacological active component found in Rheum palmatum L. that is the major herb of the San-Huang-Xie-Xin-Tang (SHXXT), a medicinal herbal product used as a remedy for constipation. Here we have investigated the comparative pharmacokinetics of rhein in normal and constipated rats. Microarray analysis was used to explore whether drug-metabolizing genes will be altered after SHXXT treatment. MATERIALS AND METHODS The comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats was studied by liquid chromatography with electrospray ionization tandem mass spectrometry (LC-MS/MS). Gene expression profiling in drug-metabolizing genes after SHXXT treatment was investigated by microarray analysis and real-time polymerase chain reaction (RT-PCR). RESULTS A validated LC-MS/MS method was applied to investigate the comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats. The pharmacokinetic results demonstrate that the loperamide-induced constipation reduced the absorption of rhein. Cmax significantly reduced by 2.5-fold, the AUC decreased by 27.8%; however, the elimination half-life (t1/2) was prolonged by 1.6-fold. Tmax and mean residence time (MRT) were significantly prolonged by 2.8-fold, and 1.7-fold, respectively. The volume of distribution (Vss) increased by 2.2-fold. The data of microarray analysis on gene expression indicate that five drug-metabolizing genes, including Cyp7a1, Cyp2c6, Ces2e, Atp1b1, and Slc7a2 were significantly altered by the SHXXT (0.5 g/kg) treatment. CONCLUSION The loperamide-induced constipation reduced the absorption of rhein. Since among the 25,338 genes analyzed, there were five genes significantly altered by SHXXT treatment. Thus, information on minor drug-metabolizing genes altered by SHXXT treatment indicates that SHXXT is relatively safe for clinical application.

中文翻译：

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大黄酸在正常和洛哌丁胺诱导的便秘大鼠中的比较药代动力学和药物代谢基因的微阵列分析。

人种药的相关性大黄是在大黄中发现的药理活性成分，大黄是三黄泻心汤（SHXXT）的主要药草，该药是一种便秘药物。在这里，我们研究了大黄酸在正常和便秘大鼠中的比较药代动力学。微阵列分析用于探讨SHXXT治疗后药物代谢基因是否会改变。材料与方法采用电喷雾电离串联质谱（LC-MS / MS），研究了大黄酸在正常大鼠和洛哌丁胺诱发的便秘大鼠中的比较药代动力学。通过微阵列分析和实时聚合酶链反应（RT-PCR）研究了SHXXT处理后药物代谢基因中的基因表达谱。结果采用验证的LC-MS / MS方法研究大黄酸在正常和洛哌丁胺诱发的便秘大鼠中的比较药代动力学。药代动力学结果表明洛哌丁胺引起的便秘减少了大黄酸的吸收。Cmax明显降低了2.5倍，AUC降低了27.8％；但是，消除半衰期（t1 / 2）延长了1.6倍。Tmax和平均停留时间（MRT）分别显着延长了2.8倍和1.7倍。分配量（Vss）增加了2.2倍。基因表达的微阵列分析数据表明，SHXXT（0.5 g / kg）处理显着改变了5个药物代谢基因，包括Cyp7a1，Cyp2c6，Ces2e，Atp1b1和Slc7a2。结论洛哌丁胺引起的便秘减少了大黄酸的吸收。由于分析的25,338个基因中，有5个基因被SHXXT处理显着改变。因此，有关通过SHXXT治疗改变的次要药物代谢基因的信息表明，SHXXT对于临床应用而言是相对安全的。