Metabolomic botanical standardization for pharmacokinetic interactions

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 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.