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

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 (V_T ) of (R)-[¹¹ C]verapamil in whole-brain grey matter was not significantly different between the elderly (V_T = 0.78 ± 0.15) and young (V_T = 0.79 ± 0.10) group. After partial (incomplete) ABCB1 inhibition, V_T values were significantly higher (P = 0.040) in the elderly (V_T = 1.08 ± 0.15) than in the young (V_T = 0.80 ± 0.18) group. The percentage increase in (R)-[¹¹ C]verapamil V_T 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.