Martin Bauer1, Beatrix Wulkersdorfer1, Rudolf Karch2, Cécile Philippe3, Walter Jäger4, Johann Stanek1,5, Wolfgang Wadsak3,6, Marcus Hacker3, Markus Zeitlinger1, Oliver Langer1,3,5. 1. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 2. Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria. 3. Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria. 4. Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria. 5. Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria. 6. Centre for Biomarker Research in Medicine - CBmed GmbH, Graz, Austria.
Abstract
AIMS: 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)-[11 C]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)-[11 C]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, VT values 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)-[11 C]verapamil VT following 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.
AIMS: 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)-[11 C]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)-[11 C]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, VT values 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)-[11 C]verapamil VT following 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.
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