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Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

Bauer M, Römermann K, Karch R, Wulkersdorfer B, Stanek J, Philippe C, Maier-Salamon A, Haslacher H, Jungbauer C, Wadsak W, Jäger W, Löscher W, Hacker M, Zeitlinger M, Langer O - Clin. Pharmacol. Ther. (2016)

Bottom Line: In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition.This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates.During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus

Mean time–activity curves (standardized uptake value, SUV ± SD) of [11C]elacridar (a,b) and [11C]tariquidar (c–f) in whole brain gray matter (a,c,e) and arterial plasma (b,d,f) for baseline scans (i.e., without ABCB1 inhibition) and scans during ABCB1 inhibition in c.421CC and c.421CA subjects (n = 5 per group). Brain time‐activity curves were corrected for radioactivity in the vasculature by subtraction of total radioactivity counts in arterial blood, scaled to 5% (vascular contribution to total brain volume). The same figure with log‐linear axis is provided as Supplementary Figure 2.
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cpt362-fig-0003: Mean time–activity curves (standardized uptake value, SUV ± SD) of [11C]elacridar (a,b) and [11C]tariquidar (c–f) in whole brain gray matter (a,c,e) and arterial plasma (b,d,f) for baseline scans (i.e., without ABCB1 inhibition) and scans during ABCB1 inhibition in c.421CC and c.421CA subjects (n = 5 per group). Brain time‐activity curves were corrected for radioactivity in the vasculature by subtraction of total radioactivity counts in arterial blood, scaled to 5% (vascular contribution to total brain volume). The same figure with log‐linear axis is provided as Supplementary Figure 2.

Mentions: In Figure2 representative PET images of [11C]elacridar and [11C]tariquidar in c.421CC subjects are shown. Both radiotracers showed very low brain uptake. In plasma, only a low amount of circulating radiolabeled metabolites was detected during the PET scans, both for [11C]elacridar and [11C]tariquidar. In the baseline scans the percentage of unchanged radiotracer in plasma at 60 minutes after injection was 94.6 ± 2.3% for [11C]elacridar and 89.7 ± 3.6% for [11C]tariquidar. In the second PET scan this value was not significantly different from the first scan for [11C]elacridar (94.7 ± 1.1%) and [11C]tariquidar (91.1 ± 2.7%). Plasma protein binding of [11C]elacridar and [11C]tariquidar appeared to be very high (>99%) and similar in the baseline and ABCB1 inhibition scans. However, the plasma free fractions of [11C]elacridar and [11C]tariquidar could not be reliably determined due to a high degree of nonspecific binding of both radiotracers to the filter membranes of the ultrafiltration devices. Plasma concentrations of [11C]elacridar and [11C]tariquidar were significantly (P = 0.043) increased during tariquidar infusion as compared with baseline PET scans (Figure3b,d). AUCs for plasma time–activity curves (TACs) in scans 1 and 2 are provided in Supplementary Table 1. For both radiotracers, brain concentrations of radioactivity were increased during ABCB1 inhibition (Figure3a,c). Data were analyzed using noncompartmental and compartmental modeling approaches. For compartmental modeling, a 2‐tissue‐4‐rate constant (2T4K) compartment model was used, which we have shown in our previous work to provide better fits of the data than a 1‐tissue‐2‐rate constant (1T2K) compartment model.26 For [11C]elacridar, the ratio of brain to plasma AUC (AUCR), total distribution volume (VT) calculated with Logan graphical analysis (VT (Logan)), influx rate constant of radioactivity from plasma into brain (K1) and VT calculated with 2T4K model (VT (2T4K)) were significantly increased in scan 2 as compared with scan 1 (Table1). For [11C]tariquidar, none of the outcome parameters was significantly changed in scan 2 as compared with scan 1 (Table2). Tariquidar plasma concentrations during the PET scan (average of three determinations at beginning, middle, and end of PET scan) were 2.6 ± 0.5 μmol/L for the [11C]elacridar group and 2.6 ± 1.1 μmol/L for the [11C]tariquidar group (Supplementary Table 2). There was for both radiotracers no significant correlation between changes in outcome parameters in scan 2 and tariquidar plasma concentration at time of PET.


Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

Bauer M, Römermann K, Karch R, Wulkersdorfer B, Stanek J, Philippe C, Maier-Salamon A, Haslacher H, Jungbauer C, Wadsak W, Jäger W, Löscher W, Hacker M, Zeitlinger M, Langer O - Clin. Pharmacol. Ther. (2016)

Mean time–activity curves (standardized uptake value, SUV ± SD) of [11C]elacridar (a,b) and [11C]tariquidar (c–f) in whole brain gray matter (a,c,e) and arterial plasma (b,d,f) for baseline scans (i.e., without ABCB1 inhibition) and scans during ABCB1 inhibition in c.421CC and c.421CA subjects (n = 5 per group). Brain time‐activity curves were corrected for radioactivity in the vasculature by subtraction of total radioactivity counts in arterial blood, scaled to 5% (vascular contribution to total brain volume). The same figure with log‐linear axis is provided as Supplementary Figure 2.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4979595&req=5

cpt362-fig-0003: Mean time–activity curves (standardized uptake value, SUV ± SD) of [11C]elacridar (a,b) and [11C]tariquidar (c–f) in whole brain gray matter (a,c,e) and arterial plasma (b,d,f) for baseline scans (i.e., without ABCB1 inhibition) and scans during ABCB1 inhibition in c.421CC and c.421CA subjects (n = 5 per group). Brain time‐activity curves were corrected for radioactivity in the vasculature by subtraction of total radioactivity counts in arterial blood, scaled to 5% (vascular contribution to total brain volume). The same figure with log‐linear axis is provided as Supplementary Figure 2.
Mentions: In Figure2 representative PET images of [11C]elacridar and [11C]tariquidar in c.421CC subjects are shown. Both radiotracers showed very low brain uptake. In plasma, only a low amount of circulating radiolabeled metabolites was detected during the PET scans, both for [11C]elacridar and [11C]tariquidar. In the baseline scans the percentage of unchanged radiotracer in plasma at 60 minutes after injection was 94.6 ± 2.3% for [11C]elacridar and 89.7 ± 3.6% for [11C]tariquidar. In the second PET scan this value was not significantly different from the first scan for [11C]elacridar (94.7 ± 1.1%) and [11C]tariquidar (91.1 ± 2.7%). Plasma protein binding of [11C]elacridar and [11C]tariquidar appeared to be very high (>99%) and similar in the baseline and ABCB1 inhibition scans. However, the plasma free fractions of [11C]elacridar and [11C]tariquidar could not be reliably determined due to a high degree of nonspecific binding of both radiotracers to the filter membranes of the ultrafiltration devices. Plasma concentrations of [11C]elacridar and [11C]tariquidar were significantly (P = 0.043) increased during tariquidar infusion as compared with baseline PET scans (Figure3b,d). AUCs for plasma time–activity curves (TACs) in scans 1 and 2 are provided in Supplementary Table 1. For both radiotracers, brain concentrations of radioactivity were increased during ABCB1 inhibition (Figure3a,c). Data were analyzed using noncompartmental and compartmental modeling approaches. For compartmental modeling, a 2‐tissue‐4‐rate constant (2T4K) compartment model was used, which we have shown in our previous work to provide better fits of the data than a 1‐tissue‐2‐rate constant (1T2K) compartment model.26 For [11C]elacridar, the ratio of brain to plasma AUC (AUCR), total distribution volume (VT) calculated with Logan graphical analysis (VT (Logan)), influx rate constant of radioactivity from plasma into brain (K1) and VT calculated with 2T4K model (VT (2T4K)) were significantly increased in scan 2 as compared with scan 1 (Table1). For [11C]tariquidar, none of the outcome parameters was significantly changed in scan 2 as compared with scan 1 (Table2). Tariquidar plasma concentrations during the PET scan (average of three determinations at beginning, middle, and end of PET scan) were 2.6 ± 0.5 μmol/L for the [11C]elacridar group and 2.6 ± 1.1 μmol/L for the [11C]tariquidar group (Supplementary Table 2). There was for both radiotracers no significant correlation between changes in outcome parameters in scan 2 and tariquidar plasma concentration at time of PET.

Bottom Line: In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition.This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates.During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus