Research ArticleClinical Investigations

Increased Permeability-Glycoprotein Inhibition at the Human Blood–Brain Barrier Can Be Safely Achieved by Performing PET During Peak Plasma Concentrations of Tariquidar

William C. Kreisl, Ritwik Bhatia, Cheryl L. Morse, Alicia E. Woock, Sami S. Zoghbi, H. Umesha Shetty, Victor W. Pike and Robert B. Innis
Journal of Nuclear Medicine January 2015, 56 (1) 82-87; DOI: https://doi.org/10.2967/jnumed.114.146894

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Composite neocortex time–activity curves showing brain uptake of radioactivity after 11C-dLop injection. 11C-dLop was injected at baseline (●) and during intravenous infusion of tariquidar at 2 (○) and 4 mg/kg (▲). Error bars denote SD.

  • FIGURE 2.
    FIGURE 2.

    Representative images from 11C-dLop PET scans. Images are summed from 10 to 30 min after injection. Radioligand was injected either at baseline (A) or during intravenous infusion of tariquidar at doses of 2 (B) and 4 mg/kg (C).

  • FIGURE 3.
    FIGURE 3.

    Composite neocortex time–activity curves showing brain uptake of radioactivity after 11C-dLop injection at baseline (●) and after 1,500 mg of oral tariquidar (○). Error bars denote SD.

  • FIGURE 4.
    FIGURE 4.

    Composite neocortex time–activity curves showing brain uptake of radioactivity after injection of 11C-dLop at baseline (●) and after either 1-time dose of 500 mg of disulfiram (○) or 2.5 g of disulfiram over 4 d (▲). Error bars denote SD.

  • FIGURE 5.
    FIGURE 5.

    Dose–response curve for tariquidar and uptake of 11C-dLop in composite neocortex. Conc = concentration.

Tables

  • TABLE 1

    Uptake of 11C-dLop in Composite Neocortex at Baseline and After Pharmacologic Inhibition of P-Glycoprotein

    ConditionAUC10–30 (SUV⋅min)K1 (mL⋅cm−3⋅min−1)k2 (min−1)VT (mL⋅cm−3)
    Baseline (n = 14)2.94 ± 0.660.014 ± 0.0020.012 ± 0.0021.20 ± 0.16
    Tariquidar
     4 mg/kg concurrent (n = 2)14.61 ± 2.31
     2 mg/kg concurrent (n = 10)15.34 ± 5.25*
     1,500 mg oral (n = 3)2.06 ± 0.07
     4 mg/kg delayed (n = 4)5.26 ± 2.26†0.026 ± 0.0090.010 ± 0.0012.56 ± 0.64
     6 mg/kg delayed (n = 3)10.05 ± 3.25‡0.049 ± 0.0110.013 ± 0.0013.88 ± 0.71
    Disulfiram
     500 mg (n = 3)3.13 ± 0.430.012 ± 0.0010.011 ± 0.0011.14 ± 0.03
     2,500 mg (n = 3)2.44 ± 0.120.012 ± 0.0070.008 ± 0.0031.53 ± 0.66

    • ↵* P < 0.0001 vs. baseline.

    • ↵† P = 0.06 vs. baseline.

    • ↵‡ P = 0.003 vs. baseline.

    • K1 = rate constant for brain entry; k2 = rate constant for brain efflux.

    • Data are mean ± SD.

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