Impact of Lipids on Compound Absorption: Mechanistic Studies and Modeling

脂质对化合物吸收的影响：机理研究和建模

• 批准号: 8650903
• 负责人: Rebecca L Carrier
• 金额: $ 43.39万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650903
• 关键词: Accounting; Area; Behavior; Biochemical; Biochemistry; Biological Availability; Biophysics; Caco-2 Cells; Cell Culture Techniques; Cell Membrane Permeability; Cell model; Cells; Chemical Engineering; Chemicals; Coculture Techniques; Complex; Computational Science; Coupled; Dependence; Diet; Digestion; Disease; Dose; Drug Compounding; Drug Delivery Systems; Drug Kinetics; Electron Spin Resonance Spectroscopy; Emulsions; Endocytosis; Equilibrium; Experimental Models; Food; Gastrointestinal Process; Gastrointestinal tract structure; Goals; HT29 Cells; Health; In Vitro; Ingestion; Intestinal Absorption; Intestinal Content; Intestines; Investigation; Kinetics; Knowledge; Lipids; Lymphatic; Mass Spectrum Analysis; Measures; Mediating; Medical; Membrane; Micelles; Modeling; Mucous body substance; National Institute of General Medical Sciences; Neutrons; Nutrient; Obesity; Oils; Oral; Outcome; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Process; Property; Relative (related person); Research; Route; Sampling; Scientist; Simulate; Solutions; Structure; Study models; System; Testing; Thermodynamics; Thin Layer Chromatography; Transmission Electron Microscopy; Vesicle; absorption; aqueous; base; feeding; in vivo; insight; light scattering; lipid transport; multidisciplinary; novel; nutrition; parallel processing; passive transport; uptake

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.

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质对口服化合物吸收的影响。脂质，以食物或药物输送载体的形式，可以将某些化合物的口服吸收提高数百%；然而，脂质也会导致吸收减少数倍，或者没有影响。这些影响目前无法进行定量预测，但对于药物输送、营养和包括肥胖在内的食品相关疾病具有巨大意义。虽然之前的研究已经探讨了胃肠道 (GI) 中脂质功能的具体方面，但有人提出，考虑多个并行的动态过程（化合物溶解、脂质消化、分配成胶体相、吸收）的综合系统方法将能够实现定量理解和预测。虽然人们认识到脂质消化和吸收是高度可变的、复杂的 由于在单个项目的有限研究和建模中无法完整捕获过程，因此所提出的方法是通过全面的物理和化学研究以及受控动态生物相关体外系统的建模以及对固有特性的分析来开发实验和理论框架。体内脂质消化系统可变。第一个目标是消化动力学和相关动态结构（光散射冷冻透射电子显微镜 (TEM)、小角度 X 射线和中子散射（SAXS 和 SANS））和化学（带有质谱的高性能薄层色谱法） (HPLC/MS)) 胶体物质的特征将在体外和体内进行表征。在第二个目标中，将使用代表广泛物理化学性质的统计选择的化合物来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，通过电子顺磁共振（EPR）进行表征。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，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（溶解、分配、消化、吸收）动力学的定量数学表达式将被集成到基于系统的质量平衡模型中，以最终预测脂质对脂质速率的影响。总体口服吸收和生物利用度。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：一名在基于脂质的口服药物递送方面具有实验和建模专业知识的化学工程师，一名在基于脂质的胶体系统的结构表征方面具有专业知识的物理学家，擅长脂质消化生化分析的医生、擅长微环境EPR研究的化学家、擅长药代动力学研究的药物科学家。