Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models.
Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models.
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何首乌提取物口服后不同模型大鼠多成分药动学比较研究
DOI：
10.3389/fphar.2021.655332
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhang T
中科院分区：
文献类型：
--
作者：
Ma N;Zhang Y;Sun L;Zhao Y;Ding Y;Zhang T
何首乌(PM)因其肝脏毒性副作用，在许多国家已被限制或禁止临床使用。其毒性研究已成为一个热门话题。到目前为止，PM的药代动力学研究主要集中在大黄素甲醚(2，3，5，4‘-tetrahydroxystilbene-2-O-β-D-glucoside，TSG)、大黄素、大黄素甲醚等原型化合物上，一直被认为是药效学材料或毒性作用的主要基础。然而，其II相代谢物的药代动力学研究尚未见报道，主要是因为此类代谢物的定量很难在没有参照物的情况下进行。此外，PM治疗不同病理模型的药代动力学研究也未见报道。另一方面，PM的毒性作用在被诊断为不同肝脏病理的患者中也有报道。本工作采用超高效液相色谱-串联质谱仪(UPLC-MS/MS)对PM的8种原型组分及其5种II相代谢产物进行了同时定量，并用于研究PM在两种不同肝脏病理模型(正常大鼠、α-异硫氰酸酯(ANIT)和四氯化碳(CCl4))中的药代动力学。结果表明，白藜芦醇的主要入血成分为大黄素、大黄素、大黄素甲素、大黄素-8-O-β⁃D-⁃葡萄糖苷(E-Glu)、大黄素甲素-8-O-β⁃D-⁃葡萄糖苷(P-Glu)、芦荟大黄素、没食子酸、白藜芦醇和儿茶素，其中大黄素、大黄素和儿茶素主要以II相代谢，白藜芦醇全部转化为II相代谢产物，其余均以药物原型形式代谢。同时，它们在不同模型中的药代动力学参数也有显著差异。例如，大黄素原型及其II相代谢产物的AUC(0-∞)值在ANIT组较高，其次是CCl_4组和正常组，而大黄素原型及其II相代谢物的AUC(0-∞)值在CCl_4组较高。为了进一步阐明药代动力学差异的原因，测定了肝脏中胆红素代谢酶和转运蛋白，并分析了主要化合物与AUC的相关性。TSG、芦荟大黄素与UGT1A1、BSEP、OATP1A4、OCT1、NTCP、MRP2、MDR1呈显著负相关(p<；0.01)。这些数据表明，当代谢酶和转运蛋白在肝脏中的表达受到抑制时，PM某些成分的暴露水平可能会在体内得到促进。
The clinical use of Polygonum multiflorum Thunb (PM) has been restricted or banned in many countries, due to its hepatotoxic adverse effects. Its toxicity research has become a hot topic. So far, the pharmacokinetic studies of PM, focusing on prototype compounds such as 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin, and physcion, have been considered the main basis of pharmacodynamic material or of toxic effect. However, pharmacokinetic studies of its phase II metabolites have not yet been reported, mainly because the quantifications of such metabolites are difficult to do without the reference substance. In addition, pharmacokinetic studies on different pathological models treated with PM have also not been reported. On the other hand, toxic effects of PM have been reported in patients diagnosed with different liver pathologies. In the present work, a simultaneous quantitation method for eight prototypes components of PM and their five phase II metabolites has been performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and used for the pharmacokinetic study of PM in two different liver pathological models in rats (normal, alpha-naphthylisothiocyanate (ANIT), and carbon tetrachloride (CCl4)). The results showed that the main blood-entering components of PM are TSG, emodin, physcion, emodin-8-O-β⁃D⁃glucoside (E-Glu), physcion-8-O-β⁃D⁃glucoside (P-Glu), aloe-emodin, gallic acid, resveratrol and catechin, among which TSG, emodin, and catechin were primary metabolized in phase II, while resveratrol was converted to all phase II metabolites, and the others were metabolized as drug prototypes. Meanwhile, their pharmacokinetic parameters in the different models also exhibited significant differences. For instance, the AUC (0-∞) values of the TSG prototype and its phase II metabolites were higher in the ANIT group, followed by CCl4 group and the normal group, while the AUC (0-∞) values of the emodin prototype and its phase II metabolites were higher in the CCl4 group. To further illustrate the reasons for the pharmacokinetic differences, bilirubin metabolizing enzymes and transporters in the liver were measured, and the correlations with the AUC of the main compounds were analyzed. TSG and aloe-emodin have significant negative correlations with UGT1A1, BSEP, OATP1A4, OCT1, NTCP, MRP2 and MDR1 (p < 0.01). These data suggest that when the expression of metabolic enzymes and transporters in the liver is inhibited, the exposure levels of some components of PM might be promoted in vivo.
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DOI：
10.1155/2017/9456785
发表时间：
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期刊：
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影响因子：
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影响因子：
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影响因子：
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