Abstract
<p class="ADMETabstracttext">Various efflux transporters, such as P-glycoprotein (P-gp) are now widely accepted to have profound influence on the disposition of substrates. Nevertheless, there is paucity of information about their expression and functionality in the pain relevant tissues (such as brain, spinal cord and dorsal root ganglia (DRG)) across various species. Therefore, our attempts were directed at evaluating P-gp expression in these tissues to understand its effect on the central nervous system (CNS) disposition. As a means of characterizing the normal tissue distribution of P-gp, immunohistochemistry was performed with two antibodies (C219 and H241) directed against different epitopes of MDR1 gene. Notable expression of P-gp was detected in the DRG of Sprague Dawley rat, Beagle Dog, Cynomolgous monkey as well as human. The expression of P-gp was observed in the CNS tissues with evident species differences, the expression of P-gp in human brain and spinal cord was lower than in rats and dogs but relatively comparable to that in monkeys. However, no species related differences were seen in the expression at the DRG level. Double-labelling using an antibody against a marker of endothelial cells confirmed that P-gp was exclusively localized in capillary endothelial cells. This study highlights the cross species similarities and differences in the expression of P-gp and thus serves as a vital step in understanding the translation of exposure of P-gp substrates to human.</p>
Highlights
Developing central nervous system (CNS) therapeutics has been one of the most challenging areas of drug discovery and development in the pharmaceutical industry
In vivo evidence for species differences in P-gp function has been demonstrated by Cutler et al, who found that higher concentrations of the P-gp inhibitor GF-120918 were needed in guinea pigs than in rats to achieve the same increase in brain concentrations of an undisclosed P-gp substrate [9]
The published literature on the expression of P-gp in the CNS largely focuses on its expression in the brain tissue; there is a paucity of information on its expression in other CNS tissues
Summary
Developing CNS therapeutics has been one of the most challenging areas of drug discovery and development in the pharmaceutical industry. There have been no reports on the differences in expression patterns of P-gp in brain tissues across various species. In this study our attempts were directed at evaluating the expression of P-gp in the brain, spinal cord and DRG of various species.
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