5 years ago

Effect of P-glycoprotein inhibition at the blood–brain barrier on brain distribution of (R)-[11C]verapamil in elderly vs. young subjects

Johann Stanek, Martin Bauer, Oliver Langer, Wolfgang Wadsak, Walter Jäger, Rudolf Karch, Beatrix Wulkersdorfer, Markus Zeitlinger, Marcus Hacker, Cécile Philippe
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)-[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, 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)-[11C]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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13301

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