title: In vivo induction of P-glycoprotein expression at the mouse blood-brain barrier: an intracerebral microdialysis study.
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 3 days with 5 mg/kg/day dexamethasone (DEX), a ligand of the nuclear receptor, pregnane X receptor, and a P-glycoprotein inducer. Tandem liquid chromatography mass spectrometric method was used to quantify analytes in dialysate, blood and plasma. P-glycoprotein, pregnane X receptor and Cyp3a11 (metabolizing enzyme for quinidine) protein expression in capillaries and brain homogenates 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 with vehicle-treated animals. In DEX-treated animals, P-glycoprotein expression in brain capillaries was 1.5-fold higher compared with 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. Applying microdialysis, distribution of quinidine, a P-gp substrate, in mouse brain extracellular fluid (ECF) was investigated following ligand-mediated P-glycoprotein (P-gp) induction at the blood-brain barrier (BBB). We demonstrated that a PXR agonist (dexamethasone) significantly up-regulated P-gp in brain capillaries and reduced quinidine brain ECF concentrations. Our data suggest that drug-drug interactions as a result of P-gp induction at the BBB are possible.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary N Y
authors.initials: GN
authors.lastname: Chan
authors.forename: Victor
authors.initials: V
authors.lastname: Saldivia
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Yang
authors.forename: Henrianna
authors.initials: H
authors.lastname: Pang
authors.forename: Inés
authors.initials: I
authors.lastname: de Lannoy
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D002196:Capillaries / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003627:Data Interpretation, Statistical; D003720:Densitometry; D003907:Dexamethasone / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017551:Microdialysis; D000077297:Pregnane X Receptor; D011802:Quinidine / Q000097:blood / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003907:Dexamethasone; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D011802:Quinidine
keywords: P-glycoprotein; blood-brain barrier; induction; microdialysis; pregnane X receptor; quinidine