Metabolomic botanical standardization for pharmacokinetic interactions

 描述（由申请人提供）：植物提取物被广泛用作补充和替代药物。与孤立成分的活性相反， 越来越清楚的是，植物药的有效性是由于活性化合物和植物提取物本身的其他植物化学物质之间的药代动力学（PK）相互作用。1，2，3，4，5这一观察结果要求采用整体技术来表征植物提取物的化学特征和标准化。6协同作用研究，像Birnbaum的等效线方法7接近一个整体的观点，但最终失败，因为它们仅限于一次研究不超过两种化合物。该项目旨在使用基于PK的方法评估“协同”相互作用：首先，确定植物混合物中的哪些成分增加了活性成分的生物利用度，其次，标准化提取物 根据这些成分作为一种新型的植物标记称为渗透调节（PM）标记。本文研究的植物为光果甘草（学名：Rhizoglabra L.）或欧洲甘草，与这个概念验证研究相关。G.光甘草是美国市场上最普遍的植物产品之一，长期以来一直被用作传统中药中的调和成分。8，9其植物标志物光甘草定与许多生物学特性相关，包括雌激素、抗氧化剂、抗炎活性和能量代谢的调节。10尽管高纯度光甘草定的吸收和代谢是众所周知的，光甘草定作为根粉末或全提取物给药的PK活性仍不清楚。11，12将使用细胞和无细胞测定来比较光甘草定作为粗提取物的一部分、人工级分和高纯度的生物利用度。将导致光甘草定渗透性增加的等分试样中存在的那些化合物归类为PM标记物。将使用最先进的计算机辅助技术（如定量NMR（qNMR）和1H迭代全自旋分析（HiFSA））开发多目标标准化方法。13本研究的结果不仅将增加标准化方案的生物相关性，还将为申请人提供分析技术（包括分离化学、生物学研究、NMR和质谱）方面的全面培训。

 DESCRIPTION (provided by applicant): Botanical extracts are widely used as a form of complementary and alternative medicine. In contrast to the activity of isolated constituents, it is becoming increasingly clear that the effectiveness of botanicals is due to pharmacokinetic (PK) interactions between active compounds and other phytochemicals native to the botanical extract.1,2,3,4,5 This observation calls for holistic techniques for the chemical characterization and standardization of botanical extracts.6 Synergy studies, like Birnbaum's isobole method7 approach a holistic perspective but ultimately fall short as they are limited to the investigation f no more than two compounds at a time. This project seeks to evaluate "synergy-like" interactions using PK based methods: first, to determine which constituents in a botanical mixture increase the bioavailability of the active principles and second, to standardize an extract according to those constituents as a new type of botanical marker called the permeability modulating (PM) markers. The plant to be studied, Glycyrrhiza glabra L. or European licorice, is relevant for this proof of concept study. G. glabra is one of the most pervasive botanical products on the US market and has long been used as a harmonizing ingredient in Traditional Chinese Medicine.8,9 Its botanical marker, glabridin, is associated with many biological properties including estrogenic, antioxidant, anti-inflammatory activity, and the regulation of energy metabolism.10 Though the absorption and metabolism of glabridin administered at high purity is well known, the PK activity of glabridin administered as root powder or whole extract remains unclear.11,12 Cell and cell free assays will be used to compare the bioavailability of glabridin as part of the crude extract, in artificial fractions, and at high purity. Those compound present in aliquots resulting in the increased permeability of glabridin will be classified as PM markers. A multi target standardization method will be developed using state of the art computer assisted techniques like quantitative NMR (qNMR) and 1H iterative Full Spin Analysis (HiFSA).13 The results of this study will not only increase the biological relevance of standardization protocols, but also provide the applicant with thorough training in analytical techniques including separation chemistry, biological investigation, NMR, and mass spectroscopy.