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

[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.An important potential mechanism of pharmacoresistance in people with epilepsy is inadequate access of antiepileptic drugs to their intrabrain targets. This may be caused by limited drug distribution across the blood-brain barrier (BBB) due to increased activity of multidrug efflux transporters, such as P-glycoprotein (P-gp) [1]. Recent ex vivo data suggest that the positron emission tomography (PET) radioligand [11C]flumazenil might be a P-gp substrate [2]. Currently, [11C]flumazenil is used clinically as a PET tracer for assessment of gamma-aminobutyric acid (GABA)A receptor mediated inhibition in epilepsy and to determine focus localization prior to resecti