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：（逐字从申请人的摘要）该项目的目标是 开发一系列技术来研究药物在生物体内的转运， 隔栏.从体外模型系统到体内的一系列技术 将开发动物系统。这些技术将基于 微透析取样和毛细管电泳。这些技术将 提供了在早期药物开发中进行高通量筛选的方法， 将与体内研究相关联。 一种基于泡状和细胞修饰毛细管的高通量方法 电泳（CE）将被开发。在这项技术中，囊泡，无论是 人工或生物衍生的，或细胞将被用作迁移 CE中的修饰符。供试化合物分配至囊泡或细胞中 将基于其渗透性改变测试化合物的迁移 进入囊泡或细胞。相对于正常CE的迁移变化应 与膜渗透性相关。这种方法将提供高吞吐量 通过允许同时测定混合物中化合物的渗透性。 我们也将发展使用细胞培养模型的活体微透析技术 生物屏障。细胞培养的扩散池法 确定渗透性的模型将通过在 微透析探针这将提高细胞培养的通量 通过改善系统中的质量传输技术。此外该 微透析的连续采样能力将提供动力学 测定以及平衡测量。细胞包被微透析 探针也可以重复使用。 最后，将继续进行使用微透析取样的体内研究 来研究体内生物屏障的转运。重点将放在 运输通过胃肠粘膜，通过胎盘， 血脑屏障将在所有试验中使用同一组供试化合物。 体外和体内研究，以提供体外与体内的相关性。 这些方法的发展还将提供一系列技术， 增加了复杂性但降低了吞吐量。