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Vol. 283, Issue 2, 574-580, 1997
Faculty of Pharmaceutical Sciences, The University of Tokyo,
7-3-1, Hongo, Bunkyo-ku, Tokyo, 113, Japan (H.K., H.S., A.K.,
Y.S.),
Faculty of Pharmaceutical Sciences, Tohoku University,
Aramaki aza-aoba, Aoba-ku, Sendai 980-77 Miyagi, Japan (T.T.), and
Department of Drug Metabolism and Pharmacokinetics, Novartis Pharma AG,
Basel, Switzerland (M.L.)
Recent studies suggest that P-glycoprotein located on the blood-brain
barrier restricts the brain uptake of its substrates. We examined the
role of P-glycoprotein on the restricted entry of quinidine to the
brain. Quinidine is a well known inhibitor of P-glycoprotein, although
it is not yet clarified whether quinidine is the substrate for
P-glycoprotein. Kinetic analysis of the uptake of quinidine into the
rat brain after intravenous bolus administration revealed that the net
uptake clearance is 25.5 µl/min/g brain. Intravenous administration
of SDZ PSC 833, a multidrug resistance modifier, enhanced the net
uptake clearance of quinidine by 15.7-fold. In contrast, no enhancement
by SDZ PSC 833 was observed for the brain uptake of mannitol, a marker
for the passive diffusion across the blood-brain barrier. The
elimination of [3H] quinidine from the rat brain after
microinjection into the cerebral cortex was inhibited by
preadministered unlabeled quinidine and verapamil. In addition, the
brain-to-plasma concentration ratio of quinidine at 10 min after
intravenous administration was 27.6-fold higher in mdr1a
knock-out mice than in control mice. These results suggest that
P-glycoprotein mediates the efflux of quinidine across the blood-brain
barrier, resulting in its restricted entry to the brain.
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