Stina Syvanen (1), Elizabeth C. de Lange (1), Yoshihiko Tagawa (2), Femke Froklage (3,4), Jonas Eriksson (3), Adriaan A. Lammertsma (3) and Rob A. Voskuyl (1,4)
(1) Leiden University, Leiden, The Netherlands; (2) Takeda Chemical Industries Ltd., Osaka, Japan; (3) VU University Medical Center, Amsterdam, The Netherlands; (4 ) SEIN – Epilepsy Institutes of The Netherlands Foundation, Heemstede, The Netherlands
Objectives: [11C]flumazenil positron emission tomography (PET) is used to assess GABAA receptor function in people with epilepsy and to localize epileptic foci prior to resective surgery. The binding kinetics of [11C]flumazenil is dependent on GABAA receptor density (Bmax) and affinity (KD). Recently, flumazenil was reported to be effluxed from the brain by P-glycoprotein (P-gp) [1]. It is believed that P-gp function is upregulated in epilepsy, and further that an upregulation in P-gp could alter transport of [11C]flumazenil into the brain and thereby confound interpretation of [11C]flumazenil PET. Thus, the objective of this study was to investigate if flumazenil blood-brain barrier transport and binding to GABAA receptors is altered in epileptic rats compared to controls, and whether changes in P-gp function may confound interpretation [11C]flumazenil PET.
Methods: 15 epileptic and 14 control rats underwent 2 consecutive PET scans. [11C]flumazenil was mixed with different amounts of unlabelled flumazenil to cover a wide range of receptor occupancies during the scan. Prior to the second scan, the rats were pre-treated with P-gp inhibitor tariquidar. A full pharmacokinetic model for [11C]flumazenil pharmacokinetics in plasma and brain was developed in NONMEM VI. Systematic covariate analysis was performed to identify covariates significant for changes in [11C]flumazenil transport across the blood-brain barrier as well as in Bmax and KD.
Results: GABAA receptor density, Bmax, was estimated as 44 ± 2 ng×mL-1 in the hippocampus in naïve control rats and was decreased by 12% in epileptic rats compared to controls. The receptor affinity, KD, was similar in both rat groups and was estimated as 5.9 ± 0.9 ng×mL-1. There was no difference in flumazenil transport across the blood-brain barrier between control and epileptic rats and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment decreased flumazenil transport out of the brain by 73%, confirming earlier reports of P-gp interaction, but did not influence Bmax or KD compared to the baseline scan.
Conclusions: Bmax was decreased in epileptic rats compared with controls, but no alteration in blood-brain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but Bmax and KD estimates were not influenced suggesting that [11C]flumazenil scanning is not confounded by alterations in P-gp function.
References
[1] Ishiwata K, Kawamura K, Yanai K, Hendrikse NH: In vivo evaluation of P-glycoprotein modulation of 8 PET radioligands used clinically. J Nucl Med 2007, 48(1):81-87.
Reference: PAGE 21 () Abstr 2487 [www.page-meeting.org/?abstract=2487]
Poster: CNS