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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
8R01EB000247-12
Application #
6519420
Study Section
Special Emphasis Panel (ZRG1-BMT (01))
Program Officer
Moy, Peter
Project Start
1991-06-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
12
Fiscal Year
2002
Total Cost
$148,927
Indirect Cost
Name
University of Kansas Lawrence
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Faiman, Morris D; Kaul, Swetha; Latif, Shaheen A et al. (2013) S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: a microdialysis study. Neuropharmacology 75:95-105
Whitaker, Gillian; Lunte, Craig E (2010) Investigation of microdialysis sampling calibration approaches for lipophilic analytes: doxorubicin. J Pharm Biomed Anal 53:490-6
Woo, Kristin L; Lunte, Craig E (2008) The development of multiple probe microdialysis sampling in the stomach. J Pharm Biomed Anal 48:20-6
Holovics, Heidi J; Anderson, Carter R; Levine, Barry S et al. (2008) Investigation of drug delivery by iontophoresis in a surgical wound utilizing microdialysis. Pharm Res 25:1762-70
Woo, Kristin L; Lunte, Craig E (2008) The direct comparison of health and ulcerated stomach tissue: a multiple probe microdialysis sampling approach. J Pharm Biomed Anal 48:85-91
Arnett, Stacy D; Lunte, Craig E (2007) Enhanced pH-mediated stacking of anions for CE incorporating a dynamic pH junction. Electrophoresis 28:3786-93
Arnett, Stacy D; Osbourn, Damon M; Moore, Kimberly D et al. (2005) Determination of 8-oxoguanine and 8-hydroxy-2'-deoxyguanosine in the rat cerebral cortex using microdialysis sampling and capillary electrophoresis with electrochemical detection. J Chromatogr B Analyt Technol Biomed Life Sci 827:16-25
Lucas, Laura H; Wilson, Sarah F; Lunte, Craig E et al. (2005) Concentration profiling in rat tissue by high-resolution magic-angle spinning NMR spectroscopy: investigation of a model drug. Anal Chem 77:2978-84
Gillogly, Julie A; Lunte, Craig E (2005) pH-mediated acid stacking with reverse pressure for the analysis of cationic pharmaceuticals in capillary electrophoresis. Electrophoresis 26:633-9
Hoque, Mohammed E; Arnett, Stacy D; Lunte, Craig E (2005) On-column preconcentration of glutathione and glutathione disulfide using pH-mediated base stacking for the analysis of microdialysis samples by capillary electrophoresis. J Chromatogr B Analyt Technol Biomed Life Sci 827:51-7

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