Functional evidence for P-glycoprotein at the nose-brain barrier.
OBJECTIVE
Experiments were performed to assess the brain distribution of [3H]-verapamil, including the influence of delivery route of inhibitor and substrate (nasal vs. systemic) on brain distribution. The anatomic location of P-glycoprotein (P-gp) at the nose-brain barrier also was investigated.


METHODS
Separate groups of mice were pretreated with rifampin or vehicle nasally or intravenously. [3H]-verapamil was administered either nasally or via in situ brain perfusion, and dose-response profiles were constructed for P-gp inhibition. Localization of P-gp in freshly obtained brain slices and olfactory tissue was evaluated by confocal microscopy.


RESULTS
Rifampin inhibited the P-gp-mediated efflux of [3H]-verapamil, regardless of delivery route (Imax = 62 +/- 6%). The ED50 for enhancement of [3H]-verapamil uptake by nasal rifampin was approximately 400-fold lower than for intravenous rifampin (0.16 vs. 65 mg/kg, respectively). Microscopy showed that P-gp was located in endothelial cells that line the olfactory bulb and within the olfactory epithelium.


CONCLUSIONS
Nasal delivery of rifampin enhanced brain uptake of [3H]-verapamil. The magnitude of transport inhibition was dependent on the dose and route of the inhibitor, the time after administration of the inhibitor, and the specific brain region examined. P-gp is localized to both the olfactory epithelium and the endothelial cells that surround the olfactory bulb.
Graff
Candace L
CL
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Pollack
Gary M
GM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009296:Nasal Cavity / Q000187:drug effects / Q000378:metabolism*; D009666:Nose; D012293:Rifampin / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012293:Rifampin