Chapter 2 . 1 [ 11 C ] Flumazenil brain uptake is infl uenced by the blood - brain barrier effl ux transporter P - glycoprotein

background [C]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 [C]fl umazenil is a P-gp substrate. The purpose of this study was to investigate whether [C]fl umazenil is a P-gp substrate. methods [C]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, [C]fl umazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [C]fl umazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [C]fl umazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [C]fl umazenil concentrations were compared in all animals (pharmacological inhibition model). results Mdr1a/1b dKO mice had approximately 70% higher [C]fl umazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [C]fl umazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [C]fl umazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small eff ect on plasma clearance of fl umazenil. Conclusions The present study showed that [C]fl umazenil is a P-gp substrate in rodents. Consequently, altered cerebral [C]fl umazenil uptake, as observed in epilepsy, may not refl ect solely GABAA receptor density changes but also changes in P-gp activity. 31 [C]Flumazenil brain effl ux by P-gp in rodents