title: Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.
abstract: ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Römermann
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Karch
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Wulkersdorfer
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.|Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Stanek
authors.affiliation: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Maier-Salamon
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Haslacher
authors.affiliation: Austrian Red Cross Blood Transfusion Services, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Jungbauer
authors.affiliation: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.|Medical Imaging Cluster, Medical University of Vienna, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Wadsak
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine, Hannover, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Löscher
authors.affiliation: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.|Medical Imaging Cluster, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Hacker
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Zeitlinger
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.|Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.|Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.|Medical Imaging Cluster, Medical University of Vienna, Vienna, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Langer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000493:pharmacokinetics; D000328:Adult; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014700:Verapamil / Q000378:metabolism / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000166:Acridines; D009363:Neoplasm Proteins; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D014700:Verapamil; C402343:tariquidar; C083501:Elacridar