P-Glycoprotein mediates the efflux of quinidine across the blood-brain barrier.
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 microl/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.
Kusuhara
H
H
Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113, Japan.
Suzuki
H
H
Terasaki
T
T
Kakee
A
A
Lemaire
M
M
Sugiyama
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011802:Quinidine / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D011802:Quinidine; C070272:valspodar