原位小鼠脑灌注模型的建立及其在mdr1a P-糖蛋白缺陷小鼠中的应用。

Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice.

作者信息

Dagenais C, Rousselle C, Pollack G M, Scherrmann J M

机构信息

Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, USA.

出版信息

J Cereb Blood Flow Metab. 2000 Feb;20(2):381-6. doi: 10.1097/00004647-200002000-00020.

DOI:10.1097/00004647-200002000-00020

PMID:10698076

Abstract

An in situ mouse brain perfusion model predictive of passive and carrier-mediated transport across the blood-brain barrier (BBB) was developed and applied to mdr1a P-glycoprotein (Pgp)-deficient mice [mdr1a(-/-)]. Cerebral flow was estimated from diazepam uptake. Physical integrity of the BBB was assessed with sucrose/inulin spaces; functional integrity was assessed with glucose uptake, which was saturable with a Km of approximately 17 mmol/L and Vmax of 310 mmol x 100 g(-1) x min(-1). Brain uptake of a Pgp substrate (colchicine) was significantly enhanced (two- to fourfold) in mdr1a(-/-) mice. These data suggest that the model is applicable to elucidating the effects of efflux transporters, including Pgp, on brain uptake.

摘要

建立了一种原位小鼠脑灌注模型，该模型可预测药物通过血脑屏障（BBB）的被动转运和载体介导转运，并将其应用于多药耐药蛋白1a（mdr1a）P-糖蛋白（Pgp）缺陷小鼠[mdr1a（-/-）]。通过地西泮摄取量估算脑血流量。用蔗糖/菊粉间隙评估BBB的物理完整性；用葡萄糖摄取评估功能完整性，葡萄糖摄取具有饱和性，其米氏常数（Km）约为17 mmol/L，最大反应速度（Vmax）为310 mmol×100 g-1×min-1。mdr1a（-/-）小鼠中Pgp底物（秋水仙碱）的脑摄取量显著增加（两倍至四倍）。这些数据表明，该模型适用于阐明包括Pgp在内的外排转运体对脑摄取的影响。