IN VIVO INVESTIGATIONS USING MICRODIALYSIS SAMPLING

描述：该项目的目标是开发微透析取样 决定治疗药物的因素的调查技术 生物利用度。微透析采样可持续监测 特定生物部位的化合物胞外浓度 有意识的动物。虽然最初是为脑内采样而开发的 神经化学系统，研究人员扩大了 治疗性化合物在人体内的药代动力学研究技术 血流和外周组织。这些技术将扩展到 用微透析法研究化合物在体内的转运 强调跨越生物障碍的运输。这将是 通过三个方面的开发完成：微透析探头 校正、改进的微量分析技术及其发展 微渗析取样程序。对将军的主要障碍是 微渗析采样的适用性在于缺乏分析方法 容易分析微体积、低浓度、高离子强度 所获得的样本。这一需求将在本项目中通过 快速微孔LC方法的研究进展。尤其是，快速梯度 微孔LC技术和无孔填料的使用将是 调查过了。毛细管电泳法对 透析样品的分析，尽管浓度敏感性和 与高离子样品的兼容性有限是个问题。这两个问题 将通过开发样品堆叠技术来解决 适用于高离子强度样品。此外，还有一种纳米流 将建立电喷雾接口，提供CE-MS和直接在线 微透析--MS能力。最终，微透析采样将是 用于研究治疗性化合物在生物体内的传输 障碍。在过去的资助期间开始了一些工作，研究 通过真皮和血脑屏障的运输；这项工作将 继续。将从以下方面开始重新强调药物的口服可用性 发展胃壁和肠壁的取样技术 门静脉。药物通过胎盘进入眼液 还将接受检查。

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.