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[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein

  • Froklage, Femke E1, 2
  • Syvänen, Stina3
  • Hendrikse, N Harry4
  • Huisman, Marc C4
  • Molthoff, Carla FM4
  • Tagawa, Yoshihiko5
  • Reijneveld, Jaap C1
  • Heimans, Jan J1
  • Lammertsma, Adriaan A4
  • Eriksson, Jonas4
  • de Lange, Elizabeth CM3
  • Voskuyl, Rob A2, 3
  • 1 VU University Medical Center, Department of Neurology, De Boelelaan 1117, Amsterdam, HV, 1081, The Netherlands , Amsterdam (Netherlands)
  • 2 SEIN - Epilepsy Institute in the Netherlands Foundation (SEIN), Achterweg 5, Heemstede, SW, 2103, The Netherlands , Heemstede (Netherlands)
  • 3 Leiden University, Division of Pharmacology, LACDR, Leiden, RA, 2300, The Netherlands , Leiden (Netherlands)
  • 4 VU University Medical Center, Department of Nuclear Medicine & PET Research, De Boelelaan 1117, Amsterdam, HV, 1081, The Netherlands , Amsterdam (Netherlands)
  • 5 Juso-Honmachi 2-Chome, Takeda Chemical Industries Ltd, 17-85, Yodogawa-ku, Osaka, 532-8686, Japan , Yodogawa-ku (Japan)
Published Article
EJNMMI Research
Springer (Biomed Central Ltd.)
Publication Date
Mar 28, 2012
DOI: 10.1186/2191-219X-2-12
Springer Nature


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).ResultsMdr1a/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.ConclusionsThe 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.

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