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1. Epilepsy Res. 2012 Feb 16. [Epub ahead of print]

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.

Mairinger S, Bankstahl JP, Kuntner C, Römermann K, Bankstahl M, Wanek T, Stanek
J, Löscher W, Müller M, Erker T, Langer O.

Health & Environment Department, Molecular Medicine, AIT Austrian Institute of
Technology GmbH, Seibersdorf, Austria; Department of Medicinal Chemistry,
University of Vienna, Austria; Department of Clinical Pharmacology, Medical
University of Vienna, Austria.

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.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID: 22342565 [PubMed - as supplied by publisher]