Mechanisms Underlying Drug-Diet Interactions

描述(由申请人提供)：患者间药物反应的变异性是临床实践中的一种持续并发症，可能会推迟甚至阻碍最佳治疗结果，从而对生活质量和医疗成本产生负面影响。不同的药物反应在一定程度上是由于通过吸收、分配和消除处理外来物质的个体间的差异。虽然已投入大量资源来描述与药物处置变量有关的遗传因素，但对非遗传因素的关注相对较少，非遗传因素至少是药物反应的重要决定因素。故意摄入膳食物质，如食物或补充剂，很可能构成环境中接触化学品的最大部分。由于饮食物质的监管方式与药物不同，因此在上市前不需要对这些物质的药物相互作用责任进行评估；与药物-药物相互作用相比，药物-饮食相互作用仍然研究不足、报道不足和误解。缺乏旨在对这些相互作用进行前瞻性评估的翻译研究方法，使这一知识匮乏更加严重，评估这些方法尤其具有挑战性，因为与大多数药品不同，膳食物质是由多种且往往未知的生物活性成分组成的混合物。临床药理学家和天然产物化学家之间的合作是以既省时又省钱的方式识别和描述药物-饮食相互作用的合乎逻辑的策略。这种伙伴关系是本申请的基础，该申请使用模型膳食物质水飞蓟素、十大畅销补充剂牛奶蓟的提取物和西柚汁(GFJ)来测试中心假设，即体外-体内-体内交互方法可以阐明特定的生物活性成分和潜在的药物-饮食相互作用的机制。初步数据表明，这些混合物中的成分是肠道细胞色素P450 3A(CyP3A)介导的代谢(水飞蓟素)或有机阴离子转运多肽(OATP)介导的吸收吸收(GFJ)的有效抑制剂，这两个过程是药物和饮食物质进入体内的主要门户。拟议的研究构成了为药物-饮食相互作用的前瞻性评估制定严格指南的框架。人类衍生的体外系统将被用来识别单独的生物活性成分，并恢复与单一成分和天然混合物的吸收渗透性和肠道细胞色素P3A或OATP抑制相关的可靠参数。恢复的体外参数将用于在计算机模型中开发，以预测饮食物质对全身暴露于模型药物的影响的程度，为临床研究设计提供信息。最后，计算机模型的准确性将在概念验证临床研究中进行评估。在这项工作中获得的信息将进一步利用决定药物反应的遗传和非遗传因素的现有知识，并将朝着向临床医生提供可靠信息以适当管理药物-饮食相互作用的长期目标迈进。

DESCRIPTION (provided by applicant): Interpatient variability in drug response is an ongoing complication in clinical practice that can delay, or even prevent, optimal therapeutic outcome, with consequent negative impact on quality of life and health care costs. Variable drug response is due in part to interindividual differences in processing xenobiotics via absorption, distribution, and elimination. While substantial resources have been invested in delineating genetic factors associated with variable drug disposition, comparatively less attention has been given to non-genetic factors, which are at least as important determinants of drug response. Intentional ingestion of dietary substances, as foods or supplements, likely constitutes the largest portion of environmental exposure to chemicals. Because dietary substances are not regulated in the same manner as drugs, evaluation of drug interaction liability for these substances is not required prior to marketing; compared to drug-drug interactions, drug-diet interactions remain understudied, underreported, and misunderstood. This knowledge deficit is compounded by a lack of translational research methodologies aimed at prospective evaluation of these interactions, which are especially challenging to assess because, unlike most drug products, dietary substances are mixtures, composed of multiple, and often unknown, bioactive ingredients. Partnering between clinical pharmacologists and natural products chemists is a logical strategy for identifying and characterizing drug-diet interactions in a time- and cost-efficient manner. Such a partnership is the foundation of the present application, which uses the model dietary substances silymarin, an extract of the top ten-selling supplement milk thistle, and grapefruit juice (GFJ) to test the central hypothesis that an interactive in vitro-in silico-in vivo approach can elucidate specific bioactive ingredients and mechanisms underlying drug-diet interactions. Preliminary data indicate that constituents in these mixtures are potent inhibitors of intestinal cytochrome P450 3A (CYP3A)-mediated metabolism (silymarin) or organic anion transporting polypeptide (OATP)-mediated absorptive uptake (GFJ), two important processes at the primary portal of drug and dietary substance entry into the body. The proposed studies compose a framework for developing rigorous guidelines for prospective evaluation of drug-diet interactions. Human-derived in vitro systems will be used to identify individual bioactive constituents and to recover robust parameters associated with absorptive permeability and enteric CYP3A or OATP inhibition by single constituents and the natural mixture. The in vitro parameters recovered will be used to develop in silico models to predict the magnitude of effect of the dietary substance on systemic exposure to a model drug, informing clinical study design. Finally, accuracy of the in silico models will be evaluated in proof-of-concept clinical studies. The information gained in this effort will further leverage existing knowledge of genetic and non-genetic factors that determine drug response, and will progress towards the long-term goal of providing firm information to clinicians for managing drug-diet interactions appropriately.