OtherBASIC SCIENCE INVESTIGATIONS

Tariquidar-Induced P-Glycoprotein Inhibition at the Rat Blood–Brain Barrier Studied with (R)-11C-Verapamil and PET

Jens P. Bankstahl, Claudia Kuntner, Aiman Abrahim, Rudolf Karch, Johann Stanek, Thomas Wanek, Wolfgang Wadsak, Kurt Kletter, Markus Müller, Wolfgang Löscher and Oliver Langer
Journal of Nuclear Medicine August 2008, 49 (8) 1328-1335; DOI: https://doi.org/10.2967/jnumed.108.051235

Article Figures & Data

Figures

  • FIGURE 1. 
    FIGURE 1. 

    Diagram of study set-up. After (R)-11C-verapamil PET scan 1, tariquidar (15 mg/kg, n = 5) or vehicle (n = 2) was administered intravenously and was followed by scan 2, which measured remainder of circulating activity from scan 1. At 3 h after scan 1, (R)-11C-verapamil PET scan 3 was acquired.

  • FIGURE 2. 
    FIGURE 2. 

    Time–activity curves in rat brain for (R)-11C-verapamil PET scans recorded before (□, n = 2, scan 1) and after (▪, n = 2, scan 3) administration of vehicle (A) and before (□, n = 5, scan 1) and after (▪, n = 5, scan 3) administration of tariquidar (15 mg/kg) (B). Activity concentration is expressed as mean percentage injected dose per gram (±SD).

  • FIGURE 3. 
    FIGURE 3. 

    Transversal (A and C) and sagittal (B and D) PET summation images (0–60 min) recorded before (A and B, scan 1) and after (C and D, scan 3) administration of tariquidar (15 mg/kg). The radiation scale was set from 0 to 700 kBq/mL.

  • FIGURE 4. 
    FIGURE 4. 

    Total activity concentrations in whole blood before (□, n = 5, scan 1) and after (▪, n = 5, scan 3) administration of tariquidar (15 mg/kg). Activity concentration is expressed as mean percentage injected dose per gram (±SD).

  • FIGURE 5. 
    FIGURE 5. 

    Brain time–activity curves for PET scan 2 recorded from 0 to 90 min after administration of vehicle (□, n = 2) or tariquidar, 15 mg/kg (▪, n = 5). PET scan 2 measured remainder of circulating activity from scan 1. Activity concentration is expressed as mean percentage injected dose per gram (±SD for n = 5).

  • FIGURE 6. 
    FIGURE 6. 

    Time–activity curves and fits obtained from 2T4K model in brain of 1 rat: before (A, scan 1) and after (B, scan 3) administration of tariquidar (15 mg/kg). y-axis is in logarithmic scale. ○ = time–activity curve in plasma measured; ⋄ = time–activity curve in brain volume of interest measured; ▪ = time–activity curve in brain volume of interest model.

  • FIGURE 7. 
    FIGURE 7. 

    Brain time–activity curves after administration of different tariquidar doses: 0 mg/kg (□, n = 5), 1 mg/kg (▪, n = 1), 3 mg/kg (▵, n = 1), 5 mg/kg (▴, n = 1), 7.5 mg/kg (○, n = 1), and 15 mg/kg (•, n = 5).

Tables

  • TABLE 1

    Outcome Parameters of 2T4K Model

    ParameterWithout tariquidar (n = 9)With tariquidar* (n = 5)Relative change (%)
    K1 (mL·mL−1·min−1)0.07 ± 0.03 (16)0.58 ± 0.20 (9)+711†
    k2 (min−1)0.34 ± 0.06 (69)0.27 ± 0.07 (43)−23
    k3 (min−1)0.29 ± 0.22 (395)0.37 ± 0.17 (66)+27
    k4 (min−1)0.73 ± 0.29 (225)0.66 ± 0.49 (55)−9
    DV (mL·mL−1)0.30 ± 0.08 (4)3.68 ± 0.81 (3)+1,137†
    DV (Logan) (mL·mL−1)0.32 ± 0.08 (1)3.53 ± 0.79 (1)+1,007†

    • ↵* Administered intravenously at dose of 15 mg/kg 2 h before start of PET scan.

    • ↵† Statistically significant difference (paired t test, P < 0.005). For statistical testing, only paired data from scans 1 and 3 were considered (n = 5).

    • Outcome parameters are given as mean ± SD. Mean estimated coefficient of variance in percentage for each parameter is given in parentheses.

  • TABLE 2

    Concentrations of Tariquidar in Plasma and Brain

    Tariquidar dose (mg/kg)Plasma (ng/mL)Brain (ng/mL)
    15 (n = 5)1,402 ± 2964,131 ± 1,638
    7.5 (n = 1)9112,570
    5 (n = 1)8071,584
    3 (n = 1)2661,449

    • Concentrations were determined 3 h after intravenous administration of different doses of tariquidar. For 15 mg/kg dose, data are mean ± SD.

Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Bookmark this article

Jump to section

Related Articles

Cited By...

More in this TOC Section

Similar Articles