title: The antiepileptic drug mephobarbital is not transported by P-glycoprotein or multidrug resistance protein 1 at the blood-brain barrier: a positron emission tomography study.
abstract: Aim of this study was to determine whether the carbon-11-labeled antiepileptic drug [(11)C]mephobarbital is a substrate of P-glycoprotein (Pgp) and can be used to assess Pgp function at the blood-brain barrier (BBB) with positron emission tomography (PET). We performed paired PET scans in rats, wild-type (FVB) and Mdr1a/b((-/-)) mice, before and after intravenous administration of the Pgp inhibitor tariquidar (15mg/kg). Brain-to-blood AUC(0-60) ratios in rats and brain AUC(0-60) values of [(11)C]mephobarbital in wild-type and Mdr1a/b((-/-)) mice were similar in scans 1 and 2, respectively, suggesting that in vivo brain distribution of [(11)C]mephobarbital is not influenced by Pgp efflux. Absence of Pgp transport was confirmed in vitro by performing concentration equilibrium transport assay in cell lines transfected with MDR1 or Mdr1a. PET experiments in wild-type mice, with and without pretreatment with the multidrug resistance protein (MRP) inhibitor MK571 (20mg/kg), and in Mrp1((-/-)) mice suggested that [(11)C]mephobarbital is also not transported by MRPs at the murine BBB, which was also supported by in vitro transport experiments using human MRP1-transfected cells. Our results are surprising, as phenobarbital, the N-desmethyl derivative of mephobarbital, has been shown to be a substrate of Pgp, which suggests that N-methylation abolishes Pgp affinity of barbiturates.
authors.affiliation: Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors.forename: Severin
authors.initials: S
authors.lastname: Mairinger
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Römermann
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D006801:Humans; D018374:LLC-PK1 Cells; D008618:Mephobarbital / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D008618:Mephobarbital; C095122:multidrug resistance protein 3