title: Effect of P-glycoprotein inhibition at the blood-brain barrier on brain distribution of (R)-[11C]verapamil in elderly vs. young subjects.
abstract: OBJECTIVE
  The efflux transporter P-glycoprotein (ABCB1) acts at the blood-brain barrier (BBB) to restrict the distribution of many different drugs from blood to the brain. Previous data suggest an age-associated decrease in the expression and function of ABCB1 at the BBB. In the present study, we investigated the influence of age on the magnitude of an ABCB1-mediated drug-drug interaction (DDI) at the BBB.
  
  
  METHODS
  We performed positron emission tomography scans using the model ABCB1 substrate (R)-[11C]verapamil in five young [26 ± 1 years, (mean ± standard deviation)] and five elderly (68 ± 6 years) healthy male volunteers before and after intravenous administration of a low dose of the ABCB1 inhibitor tariquidar (3 mg kg-1).
  
  
  RESULTS
  In baseline scans, the total distribution volume (VT) of (R)-[11C]verapamil in whole-brain grey matter was not significantly different between the elderly (VT= 0.78 ± 0.15) and young (VT= 0.79 ± 0.10) group. After partial (incomplete) ABCB1 inhibition, VTvalues were significantly higher (P = 0.040) in the elderly (VT= 1.08 ± 0.15) than in the young (VT= 0.80 ± 0.18) group. The percentage increase in (R)-[11C]verapamil VTfollowing partial ABCB1 inhibition was significantly greater (P = 0.032) in elderly (+40 ± 17%) than in young (+2 ± 17%) volunteers. Tariquidar plasma concentrations were not significantly different between the young (786 ± 178 nmol l-1) and elderly (1116 ± 347 nmol l-1) group.
  
  
  CONCLUSIONS
  Our results provide the first direct evidence of an increased risk for ABCB1-mediated DDIs at the BBB in elderly persons, which may have important consequences for pharmacotherapy of the elderly.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Wulkersdorfer
authors.affiliation: Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.affiliation: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Cécile
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
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: Johann
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.|Centre for Biomarker Research in Medicine - CBmed GmbH, Graz, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.affiliation: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Marcus
authors.initials: M
authors.lastname: Hacker
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.|Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.|Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000328:Adult; D000367:Age Factors; D000368:Aged; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism; D004347:Drug Interactions; D066128:Gray Matter / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000494:pharmacology*; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D002250:Carbon Radioisotopes; D011804:Quinolines; D014700:Verapamil; C402343:tariquidar
keywords: P-glycoprotein; PET; age; blood-brain barrier; drug-drug interaction