title: Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET.
abstract: The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in high concentrations at the blood-brain barrier (BBB) and is believed to be implicated in resistance to central nervous system drugs. We used small-animal PET and (R)-11C-verapamil together with tariquidar, a new-generation P-gp modulator, to study the functional activity of P-gp at the BBB of rats. To enable a comparison with human PET data, we performed kinetic modeling to estimate the rate constants of radiotracer transport across the rat BBB.
  
  
  METHODS
  A group of 7 Wistar Unilever rats underwent paired (R)-11C-verapamil PET scans at an interval of 3 h: 1 baseline scan and 1 scan after intravenous injection of tariquidar (15 mg/kg, n = 5) or vehicle (n = 2).
  
  
  RESULTS
  After tariquidar administration, the distribution volume (DV) of (R)-11C-verapamil was 12-fold higher than baseline (3.68 +/- 0.81 vs. 0.30 +/- 0.08; P = 0.0007, paired t test), whereas the DVs were essentially the same when only vehicle was administered. The increase in DV could be attributed mainly to an increased influx rate constant (K1) of (R)-11C-verapamil into the brain, which was about 8-fold higher after tariquidar. A dose-response assessment with tariquidar provided an estimated half-maximum effect dose of 8.4 +/- 9.5 mg/kg.
  
  
  CONCLUSIONS
  Our data demonstrate that (R)-11C-verapamil PET combined with tariquidar administration is a promising approach to measure P-gp function at the BBB.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Aiman
authors.initials: A
authors.lastname: Abrahim
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.forename: Kurt
authors.initials: K
authors.lastname: Kletter
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D005260:Female; D008954:Models, Biological; D049268:Positron-Emission Tomography / Q000379:methods; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014018:Tissue Distribution; D014700:Verapamil / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D011804:Quinolines; D014700:Verapamil; C402343:tariquidar