Impact of Lipids on Compound Absorption: Mechanistic Studies and Modeling

描述(由申请人提供)：该项目的总体目标是开发一个实验和理论框架，能够从机理上理解和定量预测摄入的脂类对口服化合物吸收的影响。脂类，以食物或药物输送载体的形式，可以使某些化合物的口服吸收增加几百%；然而，脂类也可以导致吸收减少几倍，或者没有影响。这些影响目前还不能定量预测，但在药物输送、营养和包括肥胖在内的与食物相关的疾病方面具有巨大的意义。虽然以前的研究已经探讨了胃肠道(GI)中脂质功能的特定方面，但有人建议，考虑多个并行的动态过程(化合物溶解、脂类消化、胶体相分配、吸收)的综合、系统的方法将使定量理解和预测成为可能。虽然人们认识到脂肪的消化和吸收是高度可变的、复杂的 对于在单个项目中有限的研究和建模不可能完全捕捉到的过程，所提出的方法是通过对受控的动态生物悬浮剂体外系统进行全面的物理和化学研究和建模，并结合对体内固有变量脂质消化系统的分析来建立实验和理论框架。在第一个目标中，将在体外和体内研究胶体物种的消化动力学及其相关的动态结构特征(光散射、低温电子显微镜(TEM)、小角X射线和中子散射(SAXS和SANS))和化学(高效薄层色谱/质谱仪(HPLC/MS))特征。在第二个目标中，将使用代表广泛物理化学性质的统计选择的化合物来研究脂类消化对化合物溶解和分配成胶体相的动力学的影响，用电子顺磁共振(EPR)表征。在第三个目标中，将在体外和体内研究脂质对肠膜通透性(细胞旁和跨细胞)和药物吸收的影响，包括被动途径和载体途径以及门脉和淋巴途径。 在第四个目标中，前三个目标中建立的描述关键过程(溶出、分配、消化、吸收)动力学的定量数学表达式将被整合到基于系统的质量平衡模型中，以最终预测脂类对总口服吸收速率和生物利用度的影响。研究团队包含了将脂肪消化的基础知识转化为定量预测所需的多学科专业知识：一名在基于脂肪的口服药物输送方面具有实验和建模专长的化学工程师，一名在基于脂质的胶体系统结构表征方面具有专长的物理学家，一名在脂质消化生化分析方面具有专长的医生，一名在微环境EPR研究方面具有专长的化学家，以及一名在药代动力学研究方面具有专长的制药科学家。 公共卫生相关性：该项目将能够定量预测口服摄入的脂类对联合给药化合物(例如，药物、营养)被人体吸收的影响。摄入的脂质，无论是来自食物还是药物输送载体，都可以导致化合物吸收的几乎十倍的积极或消极变化，但这些影响目前尚不清楚，也无法预测。拟议的项目将为预测血脂对口服吸收的影响提供一个实验和理论框架，通过为口服药物和营养补充剂提供实用、相关的指导，并对包括肥胖在内的与食物有关的疾病提供有意义的洞察，从而显著影响社会健康。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop an experimental and theoretical framework enabling mechanistic understanding and quantitative prediction of the influence of ingested lipids on orally delivered compound absorption. Lipids, in the form of food or drug delivery vehicles, can enhance oral absorption of some compounds several hundred percent; however, lipids 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, including obesity. While previous studies have probed specific aspects of lipid 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. While it is recognized that lipid digestion and absorption are highly variable, complex processes impossible to capture in their entirety in limited studies and modeling in a single project, the proposed approach is to develop an experimental and theoretical framework through comprehensive physical and chemical study and modeling of a controlled dynamic biorelevant in vitro system coupled with analysis of the inherently variable in vivo lipid digestio system. In the first aim, kinetics of digestion and associated dynamic structural (light scattering cryo-transmission electron microscopy (TEM), small angle x-ray and neutron scattering (SAXS and SANS)), and chemical (high performance thin layer chromatography with mass spectrometry (HPLC/MS)) features of colloidal species will be characterized in vitro and in vivo. In the second aim, the influence of lipid digestion on kinetics of compound dissolution and partitioning into colloidal phases, characterized using electron paramagnetic resonance (EPR), will be studied using statistically selected compounds representing broad ranges of physicochemical properties. In the third aim, the influence of lipids on intestinal membrane permeability (paracellular and transcellular) and drug absorption, considering passive and carrier-mediated as well as both portal and lymphatic routes, will be studied in vitro and in vivo. In the fourth aim, quantitative mathematical expressions developed in the first three aims to describe kinetics of key processes (dissolution, partitioning, digestion, absorption) will be integrated into a systems-based mass balance model to ultimately predict the influence of lipids on rate of overall oral absorption and bioavailability. 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, a physicist with expertise in structural characterization of lipid-based colloidal systems, a medical doctor with expertise in lipid digestion biochemical analysis, a chemist with expertise in EPR studies of microenvironment, and a pharmaceutical scientist with expertise in pharmacokinetic studies. PUBLIC HEALTH RELEVANCE: This project will enable quantitative prediction of the influence of orally ingested lipids on co-administered compound (e.g., drug, nutrient) absorption by the body. Ingested lipids, whether from food or a drug delivery vehicle, can result in almost ten-fold positive or negative changes in compound absorption, but these effects are currently poorly understood and not possible to predict. The proposed project will result in an experimental and theoretical framework for predicting the influence of lipids on oral absorption that will significantly impact societal health by providing practical, relevant guidance for orally dosing drugs and nutritive supplements and meaningful insight into food related diseases, including obesity.