Graff Candace L, Pollack Gary M
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Pharm Res. 2005 Jan;22(1):86-93. doi: 10.1007/s11095-004-9013-3.
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.
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.
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.
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.
进行实验以评估[3H] - 维拉帕米的脑内分布情况,包括抑制剂和底物给药途径(鼻腔给药与全身给药)对脑内分布的影响。同时还研究了鼻脑屏障处P - 糖蛋白(P - gp)的解剖位置。
将小鼠分为不同组,分别经鼻腔或静脉给予利福平或赋形剂进行预处理。[3H] - 维拉帕米通过鼻腔给药或原位脑灌注给药,并构建P - gp抑制的剂量 - 反应曲线。通过共聚焦显微镜评估新鲜获取的脑切片和嗅觉组织中P - gp的定位。
无论给药途径如何,利福平均能抑制P - gp介导的[3H] - 维拉帕米外排(Imax = 62±6%)。鼻腔给予利福平增强[3H] - 维拉帕米摄取的ED50比静脉给予利福平低约400倍(分别为0.16 vs. 65 mg/kg)。显微镜检查显示,P - gp位于嗅球内衬的内皮细胞以及嗅上皮内。
鼻腔给予利福平可增强[3H] - 维拉帕米的脑摄取。转运抑制的程度取决于抑制剂的剂量和给药途径、抑制剂给药后的时间以及所检查的特定脑区。P - gp定位于嗅上皮和围绕嗅球的内皮细胞。