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：（申请人摘要的逐字记录）该项目的目标是 开发一系列技术来研究药物跨生物转运 障碍。从体外模型系统到体内的一系列技术 将开发动物系统。这些技术将基于组合 微透析取样和毛细管电泳。这些技术将 提供早期药物开发中的高通量筛选方法 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）技术将得到发展。在该技术中，囊泡或者 人工或生物衍生的，或细胞将被用作迁移 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 的迁移变化应该 与膜的通透性相关。这种方法将提供高吞吐量 通过允许同时测定混合物中的化合物的渗透性。 我们还将利用细胞培养模型开发体内微透析技术 的生物屏障。使用细胞培养的扩散池方法 确定渗透性的模型将通过在其上生长细胞来修改 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来实现技术。此外， 微透析的连续采样能力将提供动力学 测定以及平衡测量。细胞涂层微透析 探针也将可重复使用。 最后，将继续使用微透析采样进行体内研究 研究体内跨生物屏障的运输。重点将放在 穿过胃肠粘膜、穿过胎盘和穿过 血脑屏障。同一组测试化合物将用于所有 体外和体内研究提供体外与体内的相关性。 这些方法的发展也将提供一系列技术 增加复杂性但降低吞吐量。