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Purpose.
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 ∼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.
Conclusion.
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.
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Graff, C., Pollack, G. Functional Evidence for P-glycoprotein at the Nose-Brain Barrier. Pharm Res 22, 86–93 (2005). https://doi.org/10.1007/s11095-004-9013-3
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DOI: https://doi.org/10.1007/s11095-004-9013-3