Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET

Eur J Nucl Med Mol Imaging. 2010 May;37(5):942-53. doi: 10.1007/s00259-009-1332-5. Epub 2009 Dec 17.

Abstract

Purpose: Overactivity of the multidrug efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is believed to play an important role in resistance to central nervous system drug treatment. (R)-[(11)C]verapamil (VPM) PET can be used to measure the function of P-gp at the BBB, but low brain uptake of VPM hampers the mapping of regional differences in cerebral P-gp function and expression. The aim of this study was to evaluate the dose-response relationship of two potent P-gp inhibitors and to investigate if increased brain uptake of VPM mediated by P-gp inhibition can be used to assess regional differences in P-gp activity.

Methods: Two groups of Sprague-Dawley rats (n = 12) underwent single VPM PET scans at 120 min after administration of different doses of the P-gp inhibitors tariquidar and elacridar. In an additional six rats, paired VPM PET scans were performed before and after administration of 3 mg/kg tariquidar.

Results: Inhibitor administration resulted in an up to 11-fold increase in VPM brain distribution volumes (DV) with half-maximum effective dose (ED(50)) values of 3.0 +/- 0.2 and 1.2 +/- 0.1 mg/kg for tariquidar and elacridar, respectively. In paired PET scans, 3 mg/kg tariquidar resulted in regionally different enhancement of brain activity distribution, with lowest DV in cerebellum and highest DV in thalamus.

Conclusion: Our data show that tariquidar and elacridar are able to increase VPM brain distribution in rat brain up to 11-fold over baseline at maximum effective doses, with elacridar being about three times more potent than tariquidar. Regional differences in tariquidar-induced modulation of VPM brain uptake point to regional differences in cerebral P-gp function and expression in rat brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Acridines / administration & dosage
  • Acridines / pharmacology*
  • Animals
  • Biological Transport / drug effects
  • Blood Proteins / metabolism
  • Blood-Brain Barrier / diagnostic imaging*
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Carbon Radioisotopes
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation / drug effects
  • Positron-Emission Tomography*
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Tetrahydroisoquinolines / administration & dosage
  • Tetrahydroisoquinolines / pharmacology*
  • Verapamil* / chemistry
  • Verapamil* / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acridines
  • Blood Proteins
  • Carbon Radioisotopes
  • Quinolines
  • Tetrahydroisoquinolines
  • Verapamil
  • tariquidar
  • Elacridar