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. 2019 May;105(5):1061-1064.
doi: 10.1002/cpt.1402. Epub 2019 Mar 23.

Imaging P-Glycoprotein Function at the Blood-Brain Barrier as a Determinant of the Variability in Response to Central Nervous System Drugs

Martin Bauer  1 , Nicolas Tournier  2 , Oliver Langer  1   3   4
Affiliations

Imaging P-Glycoprotein Function at the Blood-Brain Barrier as a Determinant of the Variability in Response to Central Nervous System Drugs

Martin Bauer et al. Clin Pharmacol Ther. 2019 May.
No abstract available

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Conflict of interest statement

The authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Representative magnetic resonance imaging‐co‐registered parametric positron emission tomography (PET) images in one subject each for (R)‐[11C]verapamil (left) and [11C]metoclopramide (right) at baseline and after P‐glycoprotein (P‐gp) inhibition either with tariquidar (infused during the PET scan at 2.3 mg/kg/hour) or with cyclosporine A (infused during the PET scan at 2.5 mg/kg/hour). In the parametric images, the intensity scales represent the outcome parameters of kinetic modeling (K 1 [mL/(cm3.minute)], influx rate constant from plasma into brain; k 2 [1/minute], efflux rate constant from brain into plasma; V T [mL/cm3], total volume of distribution). At baseline, [11C]metoclopramide had a higher brain uptake (V T, K 1) than (R)‐[11C]verapamil. For (R)‐[11C]verapamil, the increase in V T (=K 1/k 2) following P‐gp inhibition was caused by an increase in K 1, while for [11C]metoclopramide the increase in V T was mainly caused by a decrease in k 2. Note that the magnitude of the response to P‐gp inhibition cannot be compared between the two probe substrates due to the higher P‐gp inhibitory potency of tariquidar than that of cyclosporine A. The [11C]metoclopramide PET images were originally published in ref. 9, Tournier, N. et al. Impact of P‐glycoprotein function on the brain kinetics of the weak substrate 11C‐metoclopramide assessed with PET imaging in humans. J. Nucl. Med. https://doi.org/10.2967/jnumed.118.219972 (2019). Copyright © SNMMI.
Figure 2
Figure 2
Diagram depicting the principle of influx hindrance and efflux enhancement by P‐glycoprotein (P‐gp) at the blood–brain barrier. For the former, P‐gp inhibition leads to an increase in the influx rate constant from plasma into brain (K 1), while for the latter P‐gp inhibition leads to a decrease in the efflux rate constant from brain into plasma (k 2). It should be noted that both processes can occur at the same time, but efflux enhancement may only be visible when a drug reaches sufficiently high concentration levels in the brain. P‐gp, P‐glycoprotein.
See this image and copyright information in PMC

References

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