| Thakker Laboratory |
Dhiren
R
Thakker
PhD
Associate Dean for Research and Graduate Education, Ferguson Distinguished Professor |
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Thakker Lab
3311 Kerr Hall
Telephone: 919-966-8835
The Thakker laboratory was formed in 1996 and has been a productive member of the research community at the School of Pharmacy at UNC. The laboratory has published over 30 publications, including peer review journals and book chapters, and has been active participants in national scientific meetings. The research interests focus on intestinal absorption and disposition of drugs, with emphasis on transport mechanisms, both paracellular and transcellular, and interactions between drug transport and metabolism. The majority of work has employed cellular model systems, predominantly a human intestinal cell model system Caco-2, to study the role and relative contributions of each transport pathway to the overall absorptive transport of drugs across the intestine.
Previous work has centered on understanding the role of apical (luminal) transporters on absorption, such as P-glycoprotein and organic cation transporters (OCTs). Recent studies have been employed to determine the relative contributions of transcellular and paracellular transport of hydrophilic cationic drugs across Caco-2 cells, in order to better understand how these drugs are readily absorbed. These studies have provided new information on potential drug-drug interactions that may be observed in the clinic and also aid in explaining the high fraction of dose absorbed for these polar, charged molecules. Currently, the laboratory has been involved in studying the interplay between P-glycoprotein and CYP3A metabolism in the intestine on drugs that are dual substrates. It has become clear that the interplay between these processes has a profound effect on metabolism and disposition. By implementing cell based models and transgenic mouse models, the effects of P-glycoprotein on intestinal metabolism can be estimated and can provide new insight into drug-drug interaction liabilities.
In addition, work continues to understand the mechanisms that modulate the tight junctions (TJ) at the cell-cell contacts in intestinal epithelial cell monolayers, in attempts to understand established paracellular permeability enhancers and also to develop and test new novel compounds that open TJs in the intestine. This work has focused on the regulation pathways of TJ proteins, extent of modulation, reversibility, and the cytotoxicity associated with increased paracellular permeability. Currently, a high-throughput screening approach is being implemented to address libraries of compounds to identify new molecular entities that may be potent paracellular permeability enhancers.
Another focus of research has centered on CYP450 metabolizing enzymes and their developmental changes in humans. This work has been of high importance in understanding pediatric metabolism in order to provide clinicians with understanding of how to properly adjust the dose and regiment in order to maintain efficacy and reduce toxicity and drug-drug interactions. This work is ongoing and is in collaboration with the NC-Pediatric Pharmacology Research Unit.
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