Altered GABA(A) receptor density and unaltered blood–brain barrier [(11)C]flumazenil transport in drug-resistant epilepsy patients with mesial temporal sclerosis

Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood–brain barrier. This study aimed to assess whether [(11)C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [(11)C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [(11)C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [(11)C]flumazenil transport across the blood–brain barrier (K(1)/k(2)) were derived for whole brain and several regions. All parameters were compared between pre- and post-tariquidar scans. Regional results were compared between mesial temporal sclerosis and contralateral sides. Tariquidar significantly increased global K(1)/k(2) (+23%) and volume of distribution (+10%), but not nondisplaceable binding potential. At the mesial temporal sclerosis side volume of distribution and nondisplaceable binding potential were lower in hippocampus (both ∼−19%) and amygdala (both ∼−16%), but K(1)/k(2) did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [(11)C]flumazenil appears to be a (weak) P-glycoprotein substrate in humans, this does not seem to affect its role as a tracer for assessing gamma-aminobutyric acid A receptor density.