IN VIVO INVESTIGATIONS USING MICRODIALYSIS SAMPLING

使用微透析取样进行体内研究

• 批准号: 6682859
• 负责人: CRAIG E LUNTE
• 金额: $ 14.89万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2004-06-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682859
• 关键词: artificial membranes; biological transport; blood brain barrier; capillary electrophoresis; drug /agent; drug metabolism; gastric mucosa; high throughput technology; laboratory rat; liquid chromatography; mass spectrometry; membrane permeability; microdialysis; pharmacokinetics; placenta; technology /technique development; vesicle /vacuole

DESCRIPTION: (verbatim from applicant's abstract) The goal of this project is to develop a range of techniques to study drug transport across biological barriers. A continuum of techniques from in vitro model systems through in vivo animal systems will be developed. The techniques will be based on a combination of microdialysis sampling and capillary electrophoresis. These techniques will provide methods for high throughput screening in early drug development that will be correlated to in vivo studies. A high throughput method based on vesicular and cell-modified capillary electrophoresis (CE) will be developed. In this technique, vesicles, either artificial or biologically derived, or cells will be used as migration modifiers in CE. Partitioning of the test compounds into the vesicles or cells will modify the migration of the test compounds based on their permeability into the vesicle or cell. The change in migration relative to normal CE should correlate to membrane permeability. This approach will provide high throughput by allowing simultaneous permeability determinations of compounds in a mixture. We will also develop in vivo microdialysis techniques using cell culture models of biological barriers. The diffusion cell approach to using cell culture models to determine permeability will be modified by growing the cells on microdialysis probes. This will improve the throughput of cell culture techniques by improving the mass transport in the system. In addition, the continuous sampling capabilities of microdialysis will provide for kinetic determinations as well as equilibrium measurements. Cell-coated microdialysis probes will also be reusable. Finally, work will continue on the in vivo studies using microdialysis sampling to study transport across biological barriers in vivo. The focus will be on transport across the gastro-intestinal mucosa, across the placenta, and across the blood-brain-barrier. The same set of test compounds will be used in all of the in vitro and in vivo studies to provide an in vitro to in vivo correlation. The development of these methods will also provide a continuum of techniques of increasing complexity but decreasing throughput.

描述：（逐字研究来自申请人的摘要）该项目的目标是 开发一系列技术来研究跨生物学的药物运输 障碍。通过体内的体外模型系统的连续技术连续 动物系统将开发。这些技术将基于组合 微透析采样和毛细管电泳。这些技术会 提供早期药物开发中高通量筛查的方法 将与体内研究相关。 基于囊泡和细胞修饰毛细管的高通量方法 电泳（CE）将开发。在这种技术中，要么 人工或生物学衍生的人，或将细胞用作迁移 CE中的修饰符。将测试化合物分配到囊泡或细胞中 将根据测试化合物的渗透性修改测试化合物的迁移 进入囊泡或细胞。相对于正常CE的迁移的变化应 与膜渗透性相关。这种方法将提供高通量 通过允许同时确定混合物中化合物。 我们还将使用细胞培养模型开发体内微透析技术 生物屏障。使用细胞培养的扩散细胞方法 确定渗透率的模型将通过在 微透析探针。这将改善细胞培养的吞吐量 通过改善系统中的大众传输来获得技术。另外， 微透析的连续采样能力将提供动力学 确定以及平衡测量。细胞涂层的微透析 探针也将是可重复使用的。 最后，使用微透析采样将继续进行体内研究 研究体内生物屏障的运输。重点将开始 穿过胃肠粘膜，遍布胎盘，跨越 血脑屏障。所有的测试化合物集将在所有 体外和体内研究提供体内相关性的体外。 这些方法的开发还将提供一系列的技术 增加复杂性但吞吐量减少。