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

Abstract

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.

Advances in PET Imaging of P-Glycoprotein Function at the Blood-Brain Barrier

“…The study by Bankstahl et al 39 did show that the regional differences and the differences between controls and epileptic rats became somewhat more pronounced when P-gp was inhibited by a low dose of tariquidar. [ 11 C]Flumazenil, a GABA A receptor antagonist and a moderate P-gp substrate, 66 has been used to study differences between epileptic and control rats with respect to both BBB pharmacokinetics and receptor binding. 101 This study did not indicate changes at the level of BBB but rather indicated that the differences observed between the two groups were caused by changes at the GABA A receptor level.…”

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

“…1,2 Recent ex vivo and in vivo data, however, suggest that [ 11 C]flumazenil is a P-gp substrate in rodents. 3–5 It has been hypothesized that P-glycoprotein (P-gp) is upregulated in areas with epileptic activity. 6 If [ 11 C]flumazenil is indeed a P-gp substrate in humans, upregulation of P-gp at the blood–brain barrier (BBB) due to epilepsy could lead to reduced cerebral uptake of [ 11 C]flumazenil, and thus to erroneous interpretation of GABA A receptor density changes.…”

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

“…However, differences in metabolite rates could affect the radioactive concentration in blood and therefore is a potential bias on the V T * calculations. The heart ventricle image-derived input function serves for calculation of distribution volume for tracers without substantial binding in the myocardium and without important metabolism during the scan [48, 49]. Finally, we calculated V T * on a group basis rather than for individual mice, thus affording a better comparison of PET scans and the ex vivo experimental results.…”

“…We argue that the V T * index is a less biased measurement than %ID/g in this regard, as it is a steady-state index. Furthermore, [ 18 F]flumazenil is a substrate of the blood-brain barrier efflux transporter P-glycoprotein [49], we cannot rule out that anesthetics might have an actions on P-glycoprotein function, further studies in P-glycoprotein knockout animals would be needed.…”