ADMET and DMPK, Vol. 4 No. 3, 2016.
Original scientific paper
https://doi.org/10.5599/admet.4.2.305
Evaluation of P-glycoprotein expression in pain relevant tissues: understanding translation of efflux from preclinical species to human
Renu Singh Dhanikula
; Drug Metabolism and Pharmacokinetics, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Cyrla Hoffert
; 2Translational Science, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Rebecca Grant
; Translational Science, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Denis Projean
; Drug Metabolism and Pharmacokinetics, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Rosemarie Panetta
; Bioscience, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Dajan O’Donnell
; Translational Science, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Marie Roumi
; Drug Metabolism and Pharmacokinetics, AstraZeneca R&D Montreal, Montreal, Québec, Canada
Abstract
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.
Keywords
Transporter; CNS; Brain; Spinal cord; Dorsal root ganglia; immunohistochemistry
Hrčak ID:
167046
URI
Publication date:
30.9.2016.
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