title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Medicine, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria. claudia.kuntner@ait.ac.at
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Gloria
authors.initials: G
authors.lastname: Stundner
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brauner
authors.forename: Martin
authors.initials: M
authors.lastname: Meier
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Ding
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; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014700:Verapamil / Q000737:chemistry / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D014700:Verapamil; C402343:tariquidar; C083501:Elacridar