P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier

Hiroyuki Kusuhara, Hiroshi Suzuki, Tetsuya Terasaki, Atsuyuki Kakee, Michel Lemaire, Yuichi Sugiyama

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)574-580
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
Publication statusPublished - 1997 Nov 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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