Natural Product-Drug Interaction Research: The Roadmap to Best Practices

U54中心整体项目总结 评估不良天然产物(NP)-药物相互作用(NPDI)的风险至关重要，因为 NP在美国的指数级销售增长。这一努力受到相对较少的药代动力学的挑战 对促成这些相互作用的个别NP成分的了解，以及缺乏机械性 了解NP对药物处置的影响。为解决这些知识差距而对新开发机构进行的调查 由于假定相同NP的植物成分成分本身具有很大的变异性， 获得足够高质量的NP研究材料，以及向其销售NP的不同人群， 包括老年人。我们建立的天然产物药物相互作用研究卓越中心 (NaPDI Center)是由国家补充和综合健康中心(NCCIH)于2015年创建的 来解决这个公共卫生问题。由临床专家组成的跨学科研究团队 药理学、NP化学、生物医学信息学和健康通信领导了这一指控，以解决 NPDI研究独有的挑战。如此续期申请书所详述，我们会将 NaPDI中心通过设计和执行新的机械驱动的交互项目，扩展实用程序 我们的基于网络的数据存储库和公共门户，并将知识的传播扩大到国家和 国际研究界。这些活动将通过协同互动来完成 在三个已确立的科学核心(药理学、分析和信息学)和一个支配性的 管理核心。药理学核心将扩展一种创新方法，以选择三到五个高优先级 NPS作为潜在的具有临床意义的NPDI的沉淀物进行研究。分析核心将来源和完全 描述商业上有代表性的NPs的化学成分，并提供NP研究 互动项目使用的材料无掺杂物和污染物。药理学核心将设计 并进行严格的体外研究，以建立NP对药物处置的影响机制；预测 使用基于生理的药代动力学建模和模拟的NPDI的大小；以及设计和 进行临床NPDI研究。分析核心将提供对目标药物NP的定量分析 人体药代动力学样本中的化学成分和新出现的药物处置生物标志物。被解读的人 互动项目产生的数据将被转移到开发和维护的数据储存库 由信息学核心。重大发现将向科学界和其他感兴趣的社区传播 通过我们独特的公共访问门户网站，由信息学核心永久保留。所有内核将共享该任务 通过在国内和国际举办有针对性的讲习班和研讨会，扩大中心的外联活动 科学会议。由核心领导人和NCCIH官员组成的指导委员会将共同监督 与NCCIH挑选的相关领域的外部专家咨询小组合作，建立科学进步中心。

PROJECT SUMMARY OF THE OVERALL U54 CENTER Assessing the risk of adverse natural product (NP)-drug interactions (NPDIs) is of paramount importance due to the exponential NP sales growth in the US. This effort is challenged by relatively scant pharmacokinetic knowledge of individual NP constituents that precipitate these interactions and a lack of mechanistic understanding of NP effects on drug disposition. Investigations of NPDIs to address these knowledge gaps are complicated by the inherently large variability in phytoconstituent composition of supposedly the same NP, acquisition of sufficient high-quality NP study materials, and the diverse populations to which NPs are marketed, including the elderly. Our established Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center) was created by the National Center for Complementary and Integrative Heath (NCCIH) in 2015 to address this public health problem. A cross-disciplinary research team composed of experts in clinical pharmacology, NP chemistry, biomedical informatics, and health communications led the charge to address the challenges unique to NPDI research. As detailed in this renewal application, we will advance the mission of the NaPDI Center by designing and executing new mechanistically-driven Interaction Projects, expanding the utility of our web-based data repository and public portal, and broadening dissemination of knowledge to national and international research communities. These activities will be accomplished through synergistic interactions between three established scientific Cores (Pharmacology, Analytical, and Informatics) and an overarching Administrative Core. The Pharmacology Core will expand an innovative method to select three to five high priority NPs to study as precipitants of potential clinically significant NPDIs. The Analytical Core will source and fully characterize the chemical composition of commercially available, representative NPs and provide NP study materials free of adulterants and contaminants for the Interaction Projects. The Pharmacology Core will design and execute rigorous in vitro studies to establish the mechanism of NP effects on drug disposition; predict the magnitude of NPDIs using physiologically-based pharmacokinetic modeling and simulation; and design and conduct clinical NPDI studies. The Analytical Core will provide quantitative analysis of object drugs, NP constituents, and emerging drug disposition biomarkers in the human pharmacokinetic samples. The interpreted data generated from the Interaction Projects will be transferred to the data repository developed and maintained by the Informatics Core. Major findings will be disseminated to scientific and other interested communities through our unique public access web portal perpetuated by the Informatics Core. All Cores will share the task of broadening Center outreach activities through targeted workshops and symposia at national and international scientific meetings. A Steering Committee composed of Core leaders and NCCIH officials will jointly oversee Center scientific progress with an External Advisory Panel of experts in relevant fields selected by NCCIH.