[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein
1 Department of Neurology, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
2 SEIN - Epilepsy Institute in the Netherlands Foundation (SEIN), Achterweg 5, Heemstede, 2103 SW, The Netherlands
3 Division of Pharmacology, LACDR, Leiden University, PO Box 9502, Leiden, 2300 RA, The Netherlands
4 Department of Nuclear Medicine & PET Research, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
5 Takeda Chemical Industries Ltd, 17-85, Juso-Honmachi 2-Chome, Yodogawa-ku, Osaka, 532-8686, Japan
EJNMMI Research 2012, 2:12 doi:10.1186/2191-219X-2-12Published: 28 March 2012
[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.
[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).
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.
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.