title: Altered GABAA receptor density and unaltered blood-brain barrier [11C]flumazenil transport in drug-resistant epilepsy patients with mesial temporal sclerosis.
abstract: Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood-brain barrier. This study aimed to assess whether [11C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [11C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [11C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [11C]flumazenil transport across the blood-brain barrier (K1/k2) 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 K1/k2(+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 K1/k2did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [11C]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.
authors.affiliation: Department of Neurology, Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands f.froklage@vumc.nl.|Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Femke E
authors.initials: FE
authors.lastname: Froklage
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Andrey
authors.initials: A
authors.lastname: Postnov
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Maqsood M
authors.initials: MM
authors.lastname: Yaqub
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Bakker
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.|Department of Clinical Pharmacology & Pharmacy, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Emile Fi
authors.initials: EF
authors.lastname: Comans
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Schuit
authors.affiliation: Department of Anesthesiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schober
authors.affiliation: Department of Neurology, Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.|Department of Neurosurgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Demetrios N
authors.initials: DN
authors.lastname: Velis
authors.affiliation: Department of Neurology, Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: Zwemmer
authors.affiliation: Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Heimans
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.affiliation: Department of Neurology, Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl
authors.affiliation: Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Reijneveld
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004351:Drug Resistance; D004833:Epilepsy, Temporal Lobe / Q000000981:diagnostic imaging*; D005442:Flumazenil / Q000493:pharmacokinetics*; D018757:GABA Modulators / Q000493:pharmacokinetics*; D006801:Humans; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods / Q000592:standards; D011963:Receptors, GABA-A / Q000032:analysis*; D012598:Sclerosis / Q000000981:diagnostic imaging*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil
keywords: Blood–brain barrier; P-glycoprotein; flumazenil; positron emission tomography; temporal lobe epilepsy