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，以实现机械理解和定量预测摄入的脂质对口服递送的复合吸收的影响。脂质以食物或药物递送车的形式可以增强一些化合物的口服吸收。但是，脂质也可能导致吸收降低几倍，也可能没有作用。这些影响目前不适合定量预测，但在药物递送，营养和与食物有关的疾病（包括肥胖症）方面具有巨大意义。虽然先前的研究已经探究了胃肠道（GI）裂纹中脂质功能的特定方面，但建议考虑多个平行的，动态的过程（复合溶解，脂质消化，分配到胶体相，吸收，吸收）将实现定量理解和预测。虽然认识到脂质消化和吸收高度可变，但复杂 在单个项目中，在有限的研究和建模中无法全面捕获过程，该方法是通过全面的物理和化学研究以及对受控的动态生物含量的体外系统的建模以及对体内脂质脂质消化系统中固有可变的分析的分析来开发实验和理论框架的过程。在第一个目标中，消化和相关的动态结构动力学（光散射冷冻传播电子显微镜（TEM），小角度X射线和中子散射（SAXS和SANS）以及化学（高性能薄层色谱，具有质谱（HPLC/MS））特征是胶体的特征和Vivo。在第二个目标中，将使用代表宽阔的物理化学特性宽范围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到胶体相的动力学的影响。在第三个目标中，考虑被动和载体介导的和载体介导的以及门户和淋巴途径，脂质对肠膜通透性（细胞细胞和跨细胞）以及药物吸收的影响将在体外和体内研究。 在第四个目标中，在前三个目的中开发的定量数学表达式将整合到基于系统的质量平衡模型中，以描述关键过程的动力学（溶出，分配，消化，吸收），以最终预测脂质对整体口服吸收率和生物利用率的影响。 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,以及具有药代动力学研究专业知识的药物科学家。