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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.
- Source :
-
European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2010 May; Vol. 37 (5), pp. 942-53. Date of Electronic Publication: 2009 Dec 17. - Publication Year :
- 2010
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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.<br />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.<br />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.<br />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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Acridines administration & dosage
Animals
Biological Transport drug effects
Blood Proteins metabolism
Blood-Brain Barrier metabolism
Carbon Radioisotopes
Dose-Response Relationship, Drug
Female
Gene Expression Regulation drug effects
Quinolines administration & dosage
Rats
Rats, Sprague-Dawley
Stereoisomerism
Tetrahydroisoquinolines administration & dosage
ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
Acridines pharmacology
Blood-Brain Barrier diagnostic imaging
Blood-Brain Barrier drug effects
Positron-Emission Tomography
Quinolines pharmacology
Tetrahydroisoquinolines pharmacology
Verapamil chemistry
Verapamil metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1619-7089
- Volume :
- 37
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- European journal of nuclear medicine and molecular imaging
- Publication Type :
- Academic Journal
- Accession number :
- 20016890
- Full Text :
- https://doi.org/10.1007/s00259-009-1332-5