Impact of Lipids on Compound Absorption: Mechanistic Studies and Modeling

描述（由申请人提供）：本项目的总体目标是开发一个实验和理论框架，从而能够从机理上理解和定量预测摄入脂质对口服给药化合物吸收的影响。以食物或药物递送载体形式存在的脂质可以使某些化合物的口服吸收提高几百倍;然而，脂质也可能导致吸收降低几倍，或者没有影响。这些影响目前还不能进行定量预测，但对药物输送、营养和食物相关疾病（包括肥胖症）具有重大意义。虽然以前的研究已经探讨了在胃肠道（GI）的脂质功能的具体方面，它提出了一个综合的，基于系统的方法，考虑多个平行的，动态的过程（化合物溶解，脂质消化，分配成胶体相，吸收）将使定量的理解和预测。虽然认识到脂质消化和吸收是高度可变的、复杂的， 过程不可能在有限的研究和建模在一个单一的项目在其全部捕获，所提出的方法是通过全面的物理和化学研究和建模的控制动态生物相关的体外系统，加上固有的变量在体内脂质消化系统的分析，开发一个实验和理论框架。在第一个目标，动力学的消化和相关的动态结构（光散射低温透射电子显微镜（TEM），小角X射线和中子散射（SAXS和SANS）），和化学（高效薄层色谱与质谱（HPLC/MS））的胶体物种的特点将在体外和体内进行表征。在第二个目标中，将使用代表广泛的物理化学性质的统计选择的化合物，研究脂质消化对化合物溶解和分配成胶体相的动力学的影响，其特征在于使用电子顺磁共振（EPR）。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，考虑被动和载体介导以及门静脉和淋巴途径。 在第四个目标中，前三个目标中开发的描述关键过程（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，以最终预测脂质对总体口服吸收速率和生物利用度的影响。该研究团队体现了将脂质消化的基础知识转化为定量预测所需的多学科专业知识：具有脂质口服药物递送实验和建模专业知识的化学工程师，具有脂质胶体系统结构表征专业知识的物理学家，具有脂质消化生化分析专业知识的医学博士，具有微环境EPR研究专业知识的化学家，和一位具有药代动力学研究专长的药学家。 公共卫生相关性：该项目将能够定量预测口服摄入的脂质对共同给药的化合物（例如，药物，营养）被身体吸收。摄入的脂质，无论是从食物还是药物载体，都可能导致化合物吸收的近十倍的正或负变化，但这些影响目前了解甚少，无法预测。拟议的项目将产生一个实验和理论框架，用于预测脂质对口服吸收的影响，这将通过为口服给药药物和营养补充剂提供实用的相关指导，以及对包括肥胖在内的食物相关疾病的有意义的见解，对社会健康产生重大影响。

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.