IN VIVO INVESTIGATIONS USING MICRODIALYSIS SAMPLING

使用微透析取样进行体内研究

• 批准号: 2713723
• 负责人: CRAIG E LUNTE
• 金额: $ 12.81万
• 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 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2713723
• 关键词: capillary electrophoresis; drug /agent; drug metabolism; embryo /fetus pharmacology; eye pharmacology; laboratory rat; liquid chromatography; mass spectrometry; microdialysis; pharmacokinetics; placental transfer

DESCRIPTION: The goal of this project is to develop microdialysis sampling techniques for investigating the factors that determine therapeutic drug bioavailability. Microdialysis sampling enables continuous monitoring of extracellular concentrations of compounds at specific biological sites in conscious animals. While initially developed for intracerebral sampling of neurochemical systems, the investigator has expanded the utility of the technique to the study of pharmacokinetics of therapeutic compounds in the blood stream and peripheral tissues. These techniques will be expanded to use microdialysis sampling to study the transport of compounds in vivo with an emphasis on transport across biological barriers. This will be accomplished through development in three areas: microdialysis probe calibration improved microanalytical techniques and development of microdialysis sampling procedures. The major impediment to the general applicability of microdialysis sampling is the lack of analytical methods that readily analyze the microvolume, low concentration, high ionic strength samples obtained. This need will be addressed in this project through the development of fast microbore LC methods. In particular, fast gradient microbore LC techniques and the use of nonporous packing materials will be investigated. Capillary electrophoresis is particularly attractive for analysis of dialysis samples although poor concentration sensitivity and limited compatibility with highly ionic samples is problematic. Both issues will be addressed through development of sample stacking technique applicable to high ionic strength samples. In addition a nanoflow electrospray interface will be built to provide CE-MS and direct on-line microdialysis -MS capabilities. Ultimately, microdialysis sampling will be used to study the transport of therapeutic compounds across biological barriers. Some work began during the past funding period on the study of transport across the dermis and the blood-brain barrier; this work will continue. A new emphasis on oral availability of drugs will be started by developing sampling techniques for the gastric and intestinal wall and the portal vein. Drug disposition into the ocular fluid across the placenta will also be examined.

描述：本项目的目标是开发微透析采样 研究决定治疗药物的因素的技术 生物利用度 微透析采样能够连续监测 细胞外浓度的化合物在特定的生物位点， 有意识的动物 虽然最初开发用于脑内取样， 神经化学系统，研究人员已经扩大了效用， 研究治疗性化合物的药代动力学的新技术 血流和外周组织。 这些技术将扩展到 使用微透析取样来研究化合物在体内的转运， 强调跨越生物屏障的运输。 这将是 通过三个方面的发展完成：微透析探针 校准改进的微量分析技术和发展 微透析取样程序。 将军的主要障碍 微透析取样的适用性是缺乏分析方法 很容易分析微体积，低浓度，高离子强度 获得的样品。 本项目将通过以下方式满足这一需求： 开发快速微孔LC方法。 特别是，快速梯度 微孔LC技术和无孔填充材料的使用将是 研究了 毛细管电泳特别有吸引力， 分析透析样本，尽管浓度灵敏度较差， 与高离子样品的有限相容性是有问题的。 这两个问题 将通过开发样品堆积技术来解决 适用于高离子强度样品。 此外，纳米流 将建立电喷雾接口，以提供CE-MS和直接在线 微透析-MS能力。 最终，微透析采样将 用于研究治疗化合物在生物体内的转运 隔栏. 在上一个供资期间， 穿过真皮和血脑屏障;这项工作将 继续 一个新的重点口服药物的供应将开始， 发展胃和肠壁的取样技术， 门静脉 药物通过胎盘进入眼液 也将被审查。