IN VIVO MICRODIALYSIS SAMPLING FOR METABOLISM STUDIES

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The primary goal of this project is to develop new techniques to continuously monitor biochemical processes in vivo with minimal perturbation of the biological system. The approach will be to design a "biosensor" based on the technique of microdialysis. Microdialysis is performed by implanting a small length of dialysis fibre at the site of interest through which a test solution is perfused. Small molecules can diffuse through the membrane to either be delivered to or sampled from the target tissue. This "biosensor" probe is directly analogous to a capillary blood vessel. This system will maintain the integrity of the organisms, both cell and organ compartmentation as well as other physiological conditions. There is no net flow of liquid, also minimizing perturbations from the experiment. Thus the actual physiological pathways will be studied without artificial stimulation of alternative paths. The microdialysis sampling will be coupled to liquid chromatographic analysis. This provides for selective detection of several species in each sample during the in vivo experiment. Decoupling the sampling step from the analysis step offers several advantages relative to other in vivo methods. In particular the metabolism of benzene and 9-amino-1,2,3,4- tetrahydroacridine (THA) will be investigated. Benzene is the simplest aromatic but information on its metabolism may be extrapolated to more complicated molecules. These are of great interest because of the widespread human exposure to phenolic compounds from dietary, environmental and pharmaceutical sources. As much information already exists on the metabolism of benzene, it serves as a good test compound for method development. There remain several important questions about benzene metabolism that the proposed methods will help answer. Little has been reported on the metabolism of THA. As THA has been reported to be a promising therapy for Alzheimer's disease but has exhibited liver toxicity in clinical trials this information is extremely important.