Research ArticleBasic Science Investigations

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Géraldine Pottier, Solène Marie, Sébastien Goutal, Sylvain Auvity, Marie-Anne Peyronneau, Simon Stute, Raphaël Boisgard, Frédéric Dollé, Irène Buvat, Fabien Caillé and Nicolas Tournier
Journal of Nuclear Medicine February 2016, 57 (2) 309-314; DOI: https://doi.org/10.2967/jnumed.115.164350

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    11C-metoclopramide uptake assay in MDCKII cells transfected with human MDR1 or BCRP genes. 3H-prazosin, a substrate of both P-gp and BCRP, was used as positive control. Accumulation in each vial was normalized by mean uptake in absence of inhibitor. Data are percentage uptake ± SD (n = 6). ***P < 0.001. **P < 0.01. n.s = nonsignificant.

  • FIGURE 2.
    FIGURE 2.

    Representative PET images (sum from 20 to 30 min after injection, SUV units) obtained using microdose 11C-metoclopramide without (condition A) or with P-gp inhibition (condition B) compared with data obtained using metoclopramide (3 mg/kg) coinjection without (condition C) or with (condition D) P-gp inhibition (tariquidar, 8 mg/kg). Volumes of interest drawn on brain and heart blood-pool are represented as white dashed lines.

  • FIGURE 3.
    FIGURE 3.

    11C-metoclopramide PET time–activity curves obtained in brain and heart blood-pool using microdose metoclopramide without (condition A) or with P-gp inhibition (condition B) compared with data obtained using metoclopramide (3 mg/kg) coinjection without (condition C) or with (condition D) P-gp inhibition (tariquidar, 8 mg/kg). Respective plasma kinetics of parent 11C-metoclopramide in same conditions were obtained from measured arterial input function corrected from parent 11C-metoclopramide fraction in plasma.

  • FIGURE 4.
    FIGURE 4.

    Displacement experiments performed in P-gp–inhibited rats: time–activity curves obtained in brain and heart blood-pool. P-gp–inhibited rats were injected with 11C-metoclopramide (42.5 ± 6.4 MBq) along with metoclopramide, 3 mg/kg (condition D). Additional dose of metoclopramide (10 mg/kg) was injected at 30 min.

  • FIGURE 5.
    FIGURE 5.

    Representative radio–high-performance liquid chromatograms obtained in plasma and in brain of P-gp–inhibited rats 30 min after 11C-metoclopramide injection (condition D, 70 MBq; 3 mg/kg).

Tables

  • TABLE 1

    11C-Metoclopramide Outcome Parameters Estimated in Rat Brain in Each Condition Using Logan Plot Analysis and 2-Tissue-Compartment Model

    Logan plot2-tissue-compartment model
    Conditionnfp (%)VT (mL⋅cm−3) using arterial input functionV’T (mL⋅cm−3) using image-derived input functionK1 (mL⋅cm−3⋅min−1)k2 (min−1)k3 (min−1)k4 (min−1)BPND
    A512.0 ± 1.92.28 ± 0.322.46 ± 0.700.23 ± 0.110.35 ± 0.180.22 ± 0.120.09 ± 0.032.40 ± 0.78
    B414.8 ± 5.77.80 ± 1.43*8.33 ± 0.91*1.02 ± 0.34*0.66 ± 0.200.34 ± 0.090.06 ± 0.025.44 ± 0.50*
    C412.4 ± 3.02.04 ± 0.192.41 ± 0.290.36 ± 0.120.43 ± 0.100.22 ± 0.150.09 ± 0.032.21 ± 1.04
    D516.7 ± 7.46.28 ± 0.48†,‡7.13 ± 0.35†,0.73 ± 0.11†0.20 ± 0.06†,0.10 ± 0.060.07 ± 0.021.97 ± 0.40

    • ↵* Statistical significance, P < 0.05 for conditions B and C compared with condition A.

    • ↵† Statistical significance, P < 0.05 for condition D compared with condition C.

    • ↵ Statistical significance, P < 0.05, and ‡P < 0.01 for condition D compared with condition B.

    • Data are shown as mean ± SD in each condition, n is number of animals used in each group, and fP is percentage of free 11C-metoclopramide in plasma. Logan plot analysis was used to estimate total distribution volume using arterial input function (VT) or image-derived input function (V’T). 2-tissue-compartment model was used to estimate 11C-metoclopramide K1, k2, k3, k4, and BPND.

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