Impact of lipids and food on oral compound absorption: mechanistic studies and modeling

该项目的总体目标是使机械的理解和定量预测的 摄入的脂质和食物对口服递送的化合物吸收的影响。脂肪和食物可以增强 某些化合物的口服吸收率为几百%;然而，它们也可能导致几倍的 减少吸收或没有效果。这些影响目前还无法进行定量预测， 但在药物输送、营养和食物相关疾病方面具有巨大的意义。而 以前的研究已经探索了胃肠道（GI）中脂质和食物功能的特定方面， 提出了一个综合的，基于系统的方法，考虑多个并行的，动态的过程， （化合物溶解、脂质消化、分配成胶体相、吸收）将使得能够定量地测定化合物的浓度。 理解和预测。PI的实验室已经开发了一个实验和理论框架 并成功用于预测脂质（长链甘油三酯）对药物吸收的影响， 药代动力学（PK）。在这个项目中，我们将从这些初步的努力，使理解和 预测复杂食物组成和结构的影响。在第一个目标中，复杂食物的影响 结构和组成对消化和共递送化合物溶解/分配到 将研究胶体。虽然人们认识到食物的组成和结构是高度可变的， 复杂性，拟议的方法是系统地测试日益复杂的物理和 受控动态生物相关体外系统的化学性质，再加上固有的 可变的体内消化系统。研究的化合物将代表广泛的相关理化性质， 特性.在第二个目标中，将探讨脂质和食物对粘膜转运过程的影响， 详细具体而言，含有脂质消化产物的混合胆汁胶束在肠粘液中的稳定性 屏障将使用电子顺磁共振（EPR）进行研究，脂质的潜在影响 将研究共递送化合物转运的跨细胞转运，包括淋巴转运的趋势。 研究了将采用一种新的原代人肠管模型，以使粘膜可视化。 在这些研究中的接口。最后，在第三个目标中，模型预测体内PK的能力，包括 人类食物效应数据将得到验证。该研究团队体现了多学科的专业知识 必须将脂质消化的基础知识转化为定量预测：化学工程师 在基于脂质的口服药物递送、粘膜转运和工程化方面具有实验和建模专业知识， 肠道系统;具有EPR分析复杂微环境的专业知识的化学家， 先进的生物材料和器官芯片专业知识，以及代表研究和 模拟食物对口服药物递送的影响。

The overall goal of this project is to enable mechanistic understanding and quantitative prediction of the influence of ingested lipids and food on orally delivered compound absorption. Lipids and food can enhance oral absorption of some compounds several hundred percent; however, they can also cause several-fold decreases in absorption, or have no effect. These effects are not currently amenable to quantitative prediction, yet hold tremendous significance with respect to drug delivery, nutrition, and food-related diseases. While previous studies have probed specific aspects of lipid and food function in the gastrointestinal (GI) tract, it is proposed that an integrated, systems based approach considering multiple parallel, dynamic processes (compound dissolution, lipid digestion, partitioning into colloidal phases, absorption) will enable quantitative understanding and prediction. An experimental and theoretical framework has been developed by the PI's lab and used successfully to predict the impact of lipids (long chain triglycerides) on drug absorption and pharmacokinetics (PK). In this project, we will build from these initial efforts to enable understanding and prediction of the impact of complex food composition and structure. In the first aim, the impact of complex food structure and composition on kinetics of digestion and co-delivered compound dissolution/partitioning into colloids will be studied. While it is recognized that food composition and structure are highly variable and complex, the proposed approach is to systematically test the impact of increasing complexity on physical and chemical properties of a controlled dynamic biorelevant in vitro system, coupled with analysis of the inherently variable in vivo digestion system. Compounds studied will represent broad ranges of relevant physicochemical properties. In the second aim, the impact of lipids and food on mucosal transport processes will be explored in detail. Specifically, the stability of mixed bile micelles containing lipid digestion products in the intestinal mucus barrier will be studied using electron paramagnetic resonance (EPR), and the potential impact of lipid transcellular transport on co-delivered compound transport, including tendency for lymphatic transport, will be studied. A novel primary human intestinal tube model will be employed to enable visualization of the mucosal interface in these studies. Finally, in the third aim, the ability of the model to predict PK in vivo, including human food effect data, will be validated. The research team embodies the multidisciplinary expertise necessary to transform fundamental knowledge of lipid digestion to quantitative prediction: a chemical engineer with experimental and modeling expertise in lipid-based oral drug delivery, mucosal transport, and engineered intestinal systems; a chemist with expertise in EPR analysis of complex microenvironments, a bioengineer with advanced biomaterial and organ-on-chip expertise, and industrial partners representing leaders in studying and modeling food effects on oral drug delivery.