Analytical Core

分析核心（核心2）项目总结 天然产物（NP）研究材料的植物成分化学表征 是阐明药代动力学天然产物-药物相互作用（NPDI）的机制的基础。 与药物产品不同，纳米颗粒是内在复杂的混合物，其生物活性成分有很大差异 成分，品牌之间和同一品牌的批次之间。分析核心将开发 一项克服这些挑战的全面战略， 分析核心负责人Oberlies博士（NP化学家）和联合PI潘恩博士（a 临床药理学家）。分析核心的职责是：1）表征化学性质 为互动项目选择的4-6个NP的组成部分; 2）来源，获取和分析选定的 从商业供应商处获得NP，以确保为研究提供充足和高质量的研究材料 相互作用项目;和3）进行NP成分，药物及其相关代谢物的生物分析， 从互动项目中收集的药代动力学样本。第一项责任将包括： 深入文献评价，重新获取或分离参比标准品（取决于商业 可用性），并使用一套光谱学和光谱学对成分进行结构表征 工具.适当时，NP成分的关键已知体内代谢物（例如，葡萄糖醛酸苷）将是 生成的.参比标准品（单独或作为混合物）将用于体外研究， 生成相互作用矩阵，并将作为校准标准品，用于随后的NP组分生物分析， 药代动力学样本第二项职责包括为每项研究建立质量标准 NP基于表征数据，并确定合适的商业制造商/供应商， 提供符合既定标准的所需数量的研究材料。学习材料的质量 将通过分析剂量单位1）关键成分的含量均匀度，2） 关键成分，3）污染物，和4）通过溶出试验评估的剂量性能。 满足严格质量保证和质量控制的商业产品将提前到 互动项目。第三项职责将包括量化NP成分、受害者药物和相关药物。 从参与相互作用的受试者中获得的药代动力学样本中的代谢物浓度 项目沈博士和潘恩博士在药物和代谢物的生物分析方面拥有丰富的经验， 用于药代动力学分析的生物流体;他们在UW和WSU的实验室分别提供了一个互补的 采用最先进的LC-MS/MS技术的检测组合，包括NP成分和表型探针药物 仪器仪表分析核心研究者的NP化学和生物分析专业知识 这是一个为实现这一目标而设立的里程碑， 了解NPDI及其临床相关性。

PROJECT SUMMARY OF THE ANALYTICAL CORE (CORE 2) Characterization of natural product (NP) study materials with respect to the chemistry of their phytoconstituents is fundamental to the mechanistic elucidation of pharmacokinetic natural product-drug interactions (NPDIs). Unlike drug products, NPs are inherently complex mixtures that vary substantively in bioactive constituent composition, both between brands and between batches of the same brand. The Analytical Core will develop a comprehensive strategy to overcome these challenges, building upon a unique and longstanding collaboration between the Analytical Core Leader Dr. Oberlies (a NP chemist) and the Co-PI Dr. Paine (a clinical pharmacologist). The responsibilities of the Analytical Core are to 1) characterize the chemistry components of the 4-6 NPs selected for the Interaction Projects; 2) source, acquire, and analyze the selected NPs obtained from commercial vendors to assure adequate and quality supply of study materials for the Interaction Projects; and 3) conduct bioanalysis of NP constituents, drugs, and their relevant metabolites in pharmacokinetic samples collected from the Interaction Projects. The first responsibility will include an in- depth literature evaluation, acquiring or isolating de novo the reference standards (depending on commercial availability), and structurally characterizing the constituents with a suite of spectroscopy and spectrometry tools. When appropriate, key known in vivo metabolites of the NP constituents (e.g., glucuronides) will be generated. The reference standards, both individually or as admixtures, will be used for in vitro studies to generate interaction matrices and will serve as calibration standards for later bioanalysis of NP constituents in the pharmacokinetic samples. The second responsibility will include establishing specifications for each study NP based on the characterization data and identifying a suitable commercial manufacturer/vendor who can supply the required amount of study material meeting the established criteria. Quality of the study materials will be assured by analyzing of the dosage units for 1) content uniformity of the key constituents, 2) stability of the key constituents, 3) contaminants, and 4) dosage performance as assessed by dissolution testing. Commercial products that satisfy strict quality assurance and quality controls will be advanced to the Interaction Projects. The third responsibility will include quantifying NP constituent, victim drug, and relevant metabolite concentrations in pharmacokinetic samples obtained from subjects participating in the Interaction Projects. Dr. Shen and Dr. Paine have extensive experience in the bioanalysis of drugs and metabolites in biofluids for pharmacokinetic profiling; their laboratories at UW and WSU, respectively, offer a complementary portfolio of assays, including NP constituents and phenotyping probe drugs, using state-of-the-art LC-MS/MS instrumentation. The collective NP chemistry and bioanalytical expertise of the Analytical Core investigators ensures accomplishment of the milestones set forth for this Core, thereby helping to advance the understanding of NPDIs and their clinical relevance.