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.

Epilepsy Research
Severin MairingerOliver Langer

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-desmet...Continue Reading

References

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Sep 12, 2007·European Journal of Nuclear Medicine and Molecular Imaging·Aiman AbrahimOliver Langer
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Nov 17, 2009·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Claudia C WagnerOliver Langer
Mar 26, 2011·Current Drug Metabolism·Severin MairingerOliver Langer

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Citations

Feb 21, 2013·ACS Chemical Neuroscience·Stina Syvänen, Jonas Eriksson
Apr 2, 2014·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Joana BickerAmílcar Falcão
Jul 17, 2014·Drug Discovery Today. Technologies·Jens P Bankstahl
Jul 22, 2017·Frontiers in Neurology·Fei TangBjörn Bauer

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