| 1. |
- Froklage, Femke E, et al.
(författare)
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[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein.
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2, s. 12-
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Syvänen, Stina, et al.
(författare)
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Altered GABAA Receptor Density and Unaltered Blood-Brain Barrier Transport in a Kainate Model of Epilepsy : An In Vivo Study Using 11C-Flumazenil and PET.
- 2012
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:12, s. 1974-1983
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the γ-aminobutyric acid A (GABA(A)) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of (11)C-flumazenil PET in epilepsy. METHODS: The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA(A) receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive (11)C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 μg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan. RESULTS: GABA(A) receptor density, B(max), was estimated as 44 ± 2 ng⋅mL(-1) in the hippocampus and as 33 ± 2 ng⋅mL(-1) in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. B(max) was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, K(D), was similar in both rat groups and all brain regions 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 kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence B(max) or K(D), compared with baseline(.) CONCLUSION: B(max) was decreased in kainate-treated rats, compared with controls, but no alteration in the blood-brain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but B(max) estimates were not influenced, suggesting that (11)C-flumazenil scanning is not confounded by alterations in P-gp function.
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| 3. |
- Verbeek, Joost, et al.
(författare)
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[11C]phenytoin revisited : synthesis by [11C]CO carbonylation and first evaluation as a P-gp tracer in rats.
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2:1, s. 36-
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: At present, several positron emission tomography (PET) tracers are in use for imaging Pglycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [11C]phenytoin and to characterize its properties as a P-gp tracer. METHODS: [11C]CO was used to synthesize [11C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [11C]phenytoin were studied in rats. Effects of P-gp function on [11C]phenytoin uptake were assessed using predosing with tariquidar. RESULTS: [11C]phenytoin was synthesized via [11C]CO in an overall decay-corrected yield of 22 +/- 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [11C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [11C]phenytoin. CONCLUSIONS: Using [11C]CO, the radiosynthesis of [11C]phenytoin could be improved. [11C]phenytoin appeared to be a rather weak P-gp substrate.
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| 4. |
- Müllauer, Julia, et al.
(författare)
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Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood--brain barriers studied with (R)-[11C]verapamil positron emission tomography.
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET). METHODS: Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood--brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated. RESULTS: Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment. CONCLUSIONS: Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
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| 5. |
- Syvänen, Stina, et al.
(författare)
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Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate.
- 2012
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 14:1, s. 87-96
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood-brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood-brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level.
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