H. Kusuhara et al., P-GLYCOPROTEIN MEDIATES THE EFFLUX OF QUINIDINE ACROSS THE BLOOD-BRAIN-BARRIER, The Journal of pharmacology and experimental therapeutics, 283(2), 1997, pp. 574-580
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.