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, Severin; Bankstahl, Jens P.; Kuntner, Claudia; Römermann, Kerstin; Bankstahl, Marion; Wanek, Thomas; Stanek, Johann; Löscher, Wolfgang; Müller, Markus; Erker, Thomas; Langer, Oliver

doi:10.1016/j.eplepsyres.2012.01.012

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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

Severin Mairinger
- 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
- These two authors contributed equally to this study.
Jens P. Bankstahl
- Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine, Hannover, Germany
- Clinic of Nuclear Medicine, Hannover Medical School, Hannover, Germany
- These two authors contributed equally to this study.
Claudia Kuntner
- Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
Kerstin Römermann
- Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine, Hannover, Germany
Marion Bankstahl
- Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine, Hannover, Germany
Thomas Wanek
- Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
Johann Stanek
- Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
- Department of Clinical Pharmacology, Medical University of Vienna, Austria
Wolfgang Löscher
- Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine, Hannover, Germany
Markus Müller
- Department of Clinical Pharmacology, Medical University of Vienna, Austria
Thomas Erker
- Department of Medicinal Chemistry, University of Vienna, Austria
- Corresponding author at: Department of Medicinal Chemistry, University of Vienna, Austria. Tel.: +43 1 4277 550 03; fax: +43 1 4277 9 551.
Oliver Langer
- Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
- Department of Clinical Pharmacology, Medical University of Vienna, Austria

Received 14 November 2011; received in revised form 10 January 2012; accepted 22 January 2012. published online 20 February 2012.
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Summary

Aim of this study was to determine whether the carbon-11-labeled antiepileptic drug [¹¹C]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 [¹¹C]mephobarbital in wild-type and Mdr1a/b^(−/−) mice were similar in scans 1 and 2, respectively, suggesting that in vivo brain distribution of [¹¹C]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 [¹¹C]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.