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In Vivo Induction of P-Glycoprotein Expression at the Mouse Blood-Brain Barrier: An Intracerebral Microdialysis Study.


J Neurochem. 2013 Jun 18;


Authors: Chan GN, Saldivia V, Yang Y, Pang H, de Lannoy I, Bendayan R


Abstract

Intracerebral microdialysis was utilized to investigate the effect of P-glycoprotein (a drug efflux transporter) induction at the mouse blood-brain barrier (BBB) on brain extracellular fluid concentrations of quinidine, an established substrate of P-glycoprotein. Induction was achieved by treating male CD-1 mice for three days with 5 mg/kg/day dexamethasone (DEX), a ligand of the nuclear receptor, pregnane X receptor (PXR), and a P-glycoprotein inducer. LC-MS/MS method was used to quantify analytes in dialysate, blood and plasma. P-glycoprotein, PXR and Cyp3a11 (metabolizing enzyme for quinidine) protein expression in capillaries and brain homogenate was measured by immunoblot analysis. Following quinidine i.v. administration, the average ratio of unbound quinidine concentrations in brain extracellular fluid (determined from dialysate samples) to plasma at steady state (375-495 min) or Kp, uu, ECF /Plasma in the DEX-treated animals was 2.5-fold lower compared to vehicle-treated animals. In DEX-treated animals, P-glycoprotein expression in brain capillaries was 1.5-fold higher compared to vehicle-treated animals while Cyp3a11 expression in brain capillaries was not significantly different between the two groups. These data demonstrate that P-gp induction mediated by DEX at the BBB can significantly reduce quinidine brain extracellular fluid concentrations by decreasing its brain permeability and further suggest that drug-drug interactions as a result of P-gp induction at the BBB are possible. This article is protected by copyright. All rights reserved.

PMID: 23777437 [PubMed - as supplied by publisher]