Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography

Abstract

This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.

Evaluation of Tracer Kinetic Models for Quantification of P-Glycoprotein Function using (R)-[11C]Verapamil and PET

“…A reason for this may be that although k 2 , if measured accurately, may be a more direct measure of (R)-[ 11 C]verapamil efflux and hence P-gp function, it is flow dependent, and it is more dependent on the late part of the input curve and thus on possible ingrowth of radioactive metabolites. The robustness of V d , combined with earlier findings that increased P-gp modulation with cyclosporine leads to increased V d of [ 11 C]verapamil in rodents as well as humans (Bart et al, 2003;Sasongko et al, 2005), make it a better surrogate marker for measuring P-gp function. Differences in test-retest variability between models corresponded well with differences in precision found in the simulation study.…”

“…Polar metabolites are generally not considered to enter the brain, but their high uptake in rat brain indicates either that part of this polar fraction does pass the BBB, or, less likely, that these metabolites are a product of in situ N-demethylation in the brain. (Sasongko et al, 2005), measured using the same method.…”

Characterization of P-Glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans

“…Since previously reported P-gp humanized mice did not express functional P-gp at the BBB (Sadiq et al, 2015), the hMDR1-MAC mouse is the first P-gp humanized mouse model expressing functional P-gp in brain capillaries. Furthermore, the mice may be valuable for predicting P-gpmediated drug-drug interactions at the BBB, although the effect of a P-gp inhibitor on the brain distribution of drugs is limited in a clinical setting (Sasongko et al, 2005;Hsiao et al, 2006;Muzi et al, 2009;Wagner et al, 2009;Bauer et al, 2015).…”

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“…The two tracers that are more commonly used for PET are 82 Rb and 68 Ga-ethylenediaminetetra-acetic acid; however, the BBB permeability of compounds labelled with other positron-emitting labels, such as 11 C (Gulyas et al 2002) and 18 F (Langen et al 2005), has also been assessed using this technique. Most recently, PET has been used to measure the kinetics of 11 C verapamil and 11 C carvedilol brain uptake, and has been shown to be a sensitive tool for measuring invivo P-gp function at the BBB in both rodents and humans (Bart et al 2005;Luurtsema et al 2005;Sasongko et al 2005). This technique may provide a benefit in screening the brain uptake of other P-gp substrates using inhibition experiments (Bickel 2005).…”