title: [11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein.
abstract: BACKGROUND
  [11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate.
  
  
  METHODS
  [11C]Flumazenil PET scans were performed in wild type (WT) (n = 9) and Mdr1a/1b, (the genes that encode for P-gp) double knockout (dKO) (n = 10) mice, and in naive rats (n = 10). In parallel to PET scanning, [11C]flumazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [11C]flumazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [11C]flumazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [11C]flumazenil concentrations were compared in all animals (pharmacological inhibition model).
  
  
  RESULTS
  Mdr1a/1b dKO mice had approximately 70% higher [11C]flumazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [11C]flumazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [11C]flumazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small effect on plasma clearance of flumazenil.
  
  
  CONCLUSIONS
  The present study showed that [11C]flumazenil is a P-gp substrate in rodents. Consequently, altered cerebral [11C]flumazenil uptake, as observed in epilepsy, may not reflect solely GABAA receptor density changes but also changes in P-gp activity.
authors.affiliation: Division of Pharmacology, LACDR, Leiden University, PO Box 9502, Leiden, 2300 RA, The Netherlands. s.syvanen@lacdr.leidenuniv.nl.
authors.forename: Femke E
authors.initials: FE
authors.lastname: Froklage
authors.forename: Stina
authors.initials: S
authors.lastname: Syvänen
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: Marc C
authors.initials: MC
authors.lastname: Huisman
authors.forename: Carla Fm
authors.initials: CF
authors.lastname: Molthoff
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Reijneveld
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Heimans
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.forename: Elizabeth Cm
authors.initials: EC
authors.lastname: de Lange
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl