Pharmacology Core

药理学核心项目总结 植物和其他天然产品（NPs）的销售继续呈指数级增长，增加了对 NP与伴随处方药之间的不良相互作用。在最初的四年多里， 天然产物药物相互作用研究卓越中心（NaPDI中心），药理学 核心建立了一个框架，用于选择，优先考虑和评估高影响力的NP作为沉淀剂 潜在的临床显著药代动力学NP-药物相互作用（NPDI），可能导致次优 治疗结果。我们采用了一种严格的、系统的“预测、学习和确认”方法， 人体相关的体外系统、药代动力学建模和模拟以及临床评价，以评估 NPDI的临床意义。本更新申请的药理学核心部分提出了三个 具体目标，完善和扩展在初始供资期间开发的“最佳实践”。目标1： 药理学核心，与分析核心，信息学核心，行政核心， 指导委员会将选择并优先考虑三到五个广泛使用的NP作为潜在的临床应用的沉淀剂。 使用我们建立的称为支点模型的方法，根据我们迄今为止的经验，我们 我已经扩展了这一创新模式，包括一个快速通道选项，以适应新兴的NP， 提高NPDI风险，以保持对公共卫生需求的反应。提出了以下高优先级的国家方案： kratom，大麻产品，肉桂，黑胡椒补充剂，和组合产品紫锥花 紫花苜蓿/白毛茛。目的2：药理学核心将使用以下方法评价这些NP的NPDI责任 建立了用于药物代谢酶和转运蛋白活性的人体外系统，并在体外对 体内外推法由食品和药物管理局推荐。目的3：药理学 核心将评估健康志愿者的临床NPDI风险，包括更脆弱的老年人 人口针对后一组的理由是，特定的纳米颗粒越来越多地销售给老年人 人口，往往声称比处方药的副作用少。药理学核心的临床 研究能力是NaPDI中心的基石，在2005年期间完成了五项临床研究。 初始融资期。在整个拟议的项目中，从R21赠款中出现的NP将被 适用于我们扩展的支点模型，并可能进入我们的NP列表。我们将不断整合新的 临床研究方法，如评估肠道微生物群的影响和纳入转运蛋白 药物代谢酶和转运蛋白的探针混合物和生物标志物。药理学核心，在 与NaPDI中心其他核心的协同作用，有效和明确地建立了一个新的标准， 不扩散和裁军倡议研究。凭借我们世界级团队的发展势头，我们有信心继续保持这一势头。 通过创新NPDI研究的其他推荐方法和确定新的临床方法， 相关的NPDIs。

PROJECT SUMMARY OF THE PHARMACOLOGY CORE Sales of botanical and other natural products (NPs) continue to rise exponentially, increasing concerns for adverse interactions between NPs and concomitant prescription medications. During the first four-plus years of our Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), the Pharmacology Core established a framework for the selection, prioritization, and evaluation of high impact NPs as precipitants of potential clinically significant pharmacokinetic NP-drug interactions (NPDIs) that could lead to suboptimal therapeutic outcomes. We adopted a rigorous, systematic ‘predict, learn, and confirm’ approach involving robust human-relevant in vitro systems, pharmacokinetic modeling and simulation, and clinical evaluation to assess the clinical relevance of NPDIs. The Pharmacology Core component of this renewal application proposes three SPECIFIC AIMS that refine and extend the ‘best practices’ developed during the initial funding period. AIM 1: the Pharmacology Core, in collaboration with the Analytical Core, Informatics Core, Administrative Core, and Steering Committee, will select and prioritize three to five widely used NPs as precipitants of potential clinically significant NPDIs using our established method termed the fulcrum model. Based on our experience to date, we have expanded this innovative model to include a fast track option that accommodates emerging NPs with heightened NPDI risk to remain responsive to public health needs. The following high priority NPs are proposed: kratom, hemp products, cinnamon, black pepper supplement, and the combination product Echinacea purpurea/goldenseal. AIM 2: the Pharmacology Core will evaluate the NPDI liability of these NPs using established human in vitro systems for both drug metabolizing enzyme and transporter activity and in vitro to in vivo extrapolation approaches recommended by the Food and Drug Administration. AIM 3: the Pharmacology Core will evaluate the clinical NPDI risk in healthy volunteers that will include a more vulnerable, elderly population. The rationale for targeting the latter group is that specific NPs are increasingly marketed to the aging population, often claiming fewer side effects than prescription medications. The Pharmacology Core’s clinical research capabilities are a cornerstone of the NaPDI Center, having completed five clinical studies during the initial funding period. Throughout the proposed project, NPs that emerge from companion R21 grants will be applied to our expanded fulcrum model and potentially advanced to our NP list. We will continually integrate new clinical research methods, such as evaluating the effects of the gut microbiota and incorporating transporter probe cocktails and biomarkers of drug metabolizing enzymes and transporters. The Pharmacology Core, in synergy with the other Cores of the NaPDI Center, has efficiently and definitively established a new standard for NPDI research. Capitalizing on the momentum of our world class team, we are confident to continue this trajectory by innovating additional recommended approaches for NPDI research and identifying novel clinically relevant NPDIs.