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Vol. 58, Issue 6, 1357-1367, December 2000
Laboratory of Pharmacology and Chemistry (D.S.M.), National
Institute of Environmental Health Sciences, National Institutes of
Health, Research Triangle Park, North Carolina; Institut fur
Pharmazeutische Technologie und Biopharmazie (S.N.N., G.F.),
Heidelberg, Germany; Divisions of Gastroenterology and Clinical
Pharmacology, Department of Internal Medicine, and Department of
Research (H.G., M.T., J.D.), University Clinic (Kantonsspital
and Childrens Hospital) Basel, Switzerland
To identify specific transporters that drive xenobiotics from central
nervous system to blood, the accumulation of fluorescent drugs was
studied in isolated capillaries from rat and pig brain using confocal
microscopy and quantitative image analysis. Luminal accumulation of
daunomycin and of fluorescent derivatives of cyclosporine A (CSA) and
ivermectin was concentrative, specific, and energy-dependent (inhibition by NaCN). Transport was reduced by PSC 833, ivermectin, verapamil, CSA, and vanadate, but not by leukotriene C4
(LTC4), indicating the involvement of P-glycoprotein.
Luminal accumulation of the fluorescent organic anions sulforhodamine
101 and fluorescein methotrexate was also concentrative, specific, and
energy-dependent. LTC4, chlorodinitrobenzene, and vanadate
reduced transport of these compounds, but PSC 833 and verapamil did
not, indicating the involvement of a multidrug resistance-associated
protein (Mrp). Immunostaining localized P-glycoprotein and Mrp2 to the
luminal surface of the capillary endothelium and quantitative
polymerase chain reaction showed Mrp1 and Mrp2 expression. Finally, the
HIV protease inhibitors saquinavir and ritonavir were potent inhibitors of transport mediated by both P-glycoprotein and Mrp. These results validate a new method for studying drug transport in isolated brain
capillaries and implicate both P-glycoprotein and one or more members
of the Mrp family in drug transport from central nervous system to blood.
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