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

J Pharmacol Exp Ther. 1997 Nov;283(2):574-80.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Animals
  • Blood-Brain Barrier*
  • Brain / metabolism
  • Cyclosporins / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Quinidine / pharmacokinetics*
  • Rats
  • Rats, Wistar

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cyclosporins
  • Quinidine
  • valspodar