Analytical Core

分析核心(核心2)的项目摘要 天然产物(NP)研究材料的植物成分化学特征 是药代动力学天然产物-药物相互作用(NPDI)机理阐明的基础。 与药品不同，纳米粒子本身就是复杂的混合物，在生物活性成分上有很大的不同。 成分，既有品牌间的，也有同一品牌的批次之间的。分析核心将会发展 克服这些挑战的全面战略，建立在独特和长期的 分析核心负责人奥伯利博士(NP化学家)和共同PI的Paine博士(a 临床药理学家)。分析核心的职责是1)描述化学 为互动项目选择的4-6个NPs的组成部分；2)来源、获取和分析选定的NPs 从商业供应商处获得核动力源，以确保研究材料的充足和优质供应 相互作用项目；以及3)对NP成分、药物及其相关代谢物进行生物分析 从互动项目中收集的药代动力学样本。第一个责任将包括在- 深度文献评估，获取或分离新的参考标准(取决于商业 可获得性)，并用一套光谱学和光谱学对成分进行结构表征 工具。在适当的时候，NP成分(例如，葡萄糖醛酸苷)在体内已知的关键代谢物将是 已生成。参比标准品，无论是单独的还是混合的，都将用于体外研究 生成相互作用矩阵，并将作为校准标准，用于以后对NP组分的生物分析 药代动力学样本。第二项责任将包括为每项研究制定规范。 NP基于表征数据，并识别能够 提供符合既定标准的所需数量的学习材料。研究材料的质量 将通过分析剂量单位1)关键成分的含量均匀度，2)稳定性 关键成分，3)污染物，4)溶出度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升到 互动项目。第三项责任将包括量化NP成分、受害者药物和相关 从参与相互作用的受试者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；他们分别在密歇根大学和西德克萨斯大学的实验室提供了互补的 使用最先进的LC-MS/MS的分析组合，包括NP成分和表型探针药物 仪器仪表。分析核心研究人员的集体NP化学和生物分析专业知识 确保完成为该核心制定的里程碑，从而帮助推进 对NPDIs及其临床相关性的理解。

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.