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 bra in. Quinidine is a well known inhibitor of P-glycoprotein, although it is not yet clarified whether quinidine is the substrate for P-glycopr otein. Kinetic analysis of the uptake of quinidine into the rat brain after intravenous bolus administration revealed that the net uptake cl earance is 25.5 mu l/min/g brain. Intravenous administration of SDZ PS C 833, a multidrug resistance modifier, enhanced the net uptake cleara nce 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 pa ssive diffusion across the blood-brain barrier. The elimination of [H- 3] quinidine from the rat brain after microinjection into the cerebral cortex was inhibited by preadministered unlabeled quinidine and Verap amil. in addition, the brain-to-plasma concentration ratio of quinidin e at 10 min after intravenous administration was 27.6-fold higher in m dr1a 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.