State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
J Chromatogr A. 2012 Oct 5;1258:84-93. doi: 10.1016/j.chroma.2012.08.041. Epub 2012 Aug 17.
Although various techniques have been employed to analyze drug metabolites, the metabolism of multi-component herbal medicine has seldom been fully addressed. In contrast to chemical drugs, a number of compounds in herbal medicine could get into circulation and then be metabolized. Moreover, these compounds may have metabolic interactions which make their pharmacokinetics (PK) even more complicated. The present work aims to elucidate the multi-component pharmacokinetics of a herbal medicine, and to demonstrate how PK behaviors were altered by co-existing constituents. Licorice (Glycyrrhiza uralensis Fisch.), a most commonly used herbal medicine, was chosen as a model. A strategy was proposed to compare the PK profiles of licorice extract with those of nine single compounds. These compounds were major bioactive constituents of licorice, and represented various structural types (flavanone, chalcone, isoflavone, saponin, and coumarin). We established a segmented selected reaction monitoring LC/MS/MS method to simultaneously monitor 63 licorice metabolites in rat plasma, and obtained the PK profiles of 55 metabolites. The results indicated that interactions among licorice compounds altered their PK behaviors in 4 aspects: improvement in bioavailability for aglycones (133- and 109-fold increase for liquiritigenin and isoliquiritigenin, respectively), prolongation in system circulation for glycosides (0.3h delay in T(max) for liquiritin apioside and isoliquiritin apioside), decrease of potential toxicity for saponins such as glycyrrhizic acid, and shift in plasma distribution for phase II metabolites. This is the first attempt to systematically reveal the in vivo process of licorice. Moreover, the study indicates noticeable interactions to alter pharmacokinetics among licorice compounds, which may be characteristic for herbal medicines.
虽然已经采用了各种技术来分析药物代谢物，但很少有研究能够全面解析复方草药的代谢过程。与化学药物不同，许多草药化合物进入体内循环后会被代谢。此外，这些化合物可能存在代谢相互作用，使得它们的药代动力学（PK）更加复杂。本工作旨在阐明草药的多组分药代动力学，并展示共存成分如何改变 PK 行为。作为模型，选择了最常用的草药甘草（Glycyrrhiza uralensis Fisch.）。提出了一种策略来比较甘草提取物与 9 种单一组分的 PK 谱。这些化合物是甘草的主要生物活性成分，代表了多种结构类型（黄烷酮、查尔酮、异黄酮、皂苷和香豆素）。我们建立了一种分段选择反应监测 LC/MS/MS 方法，以同时监测大鼠血浆中的 63 种甘草代谢物，并获得了 55 种代谢物的 PK 谱。结果表明，甘草化合物之间的相互作用在 4 个方面改变了它们的 PK 行为：苷元的生物利用度提高（甘草苷元和异甘草苷元分别提高了 133 倍和 109 倍），糖苷的系统循环时间延长（甘草苷元和异甘草苷元的 Tmax 延迟 0.3h），甘草酸等皂苷的潜在毒性降低，以及 II 期代谢物在血浆中的分布发生转移。这是首次系统地揭示甘草体内过程的尝试。此外，该研究表明，甘草化合物之间存在明显的相互作用，可能是草药的特征。
