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.
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