pgp - publications

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1. EJNMMI Res. 2012 Mar 28;2(1):12. [Epub ahead of print]

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

Froklage FE, Syvanen S, Hendrikse NH, Huisman MC, Molthoff CF, Tagawa Y,
Reijneveld JC, Heimans JJ, Lammertsma AA, Eriksson J, de Lange EC, Voskuyl RA.

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).
RESULTS: 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. CONCLUSIONS: 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.

PMID: 22455873 [PubMed - as supplied by publisher]