Pharmacokinetic modelling of [18F]MC225 for quantification of P-glycoprotein function at the blood-brain barrier in non-human primates with PET

García-Varela, L., Arif, W. M., Vállez García, D., Kakiuchi, T., Ohba, H., Harada, N., Tago, T., Elsinga, P. H., Tsukada, H., Colabufo, N. A., Dierckx, R. A. J. O., van Waarde, A., Toyohara, J., Boellaard, R. & Luurtsema, G., 5-Aug-2020, In : Molecular pharmaceutics. 10 p.

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  • Pharmacokinetic Modeling of [18F]MC225 for Quantification of the P-Glycoprotein Function at the Blood–Brain Barrier in Non-Human Primates with PET

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[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood-brain barrier (BBB) with positron emission tomography (PET). This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8mg/kg tariquidar). Data were analyzed using 1-Tissue-Compartment Model (1-TCM) and 2-Tissue-Compartment Model (2-TCM) fits using metabolite-corrected plasma as input function, and for various scan durations (10-, 20-, 30-, 60- and 91-min). The preferred model was chosen according to the Akaike Information Criterion (AIC) and the standard errors (SE%) of the estimated parameters. For the 91-min scan duration, the influx constant K1 increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2 did not change significantly. Similar changes were found for all evaluated scan durations. K1 did not depend on scan duration (10-min-K1=0.2191 vs 91-min-K1=0.2258), while VT and k2 did. 10-min scan duration seems sufficient to properly evaluate the P-gp function using K1 obtained with 1-TCM. For 91-min scan, VT and K1 can be estimated with a 2-TCM and both parameters can be used to assess P-gp function.

Original languageEnglish
Number of pages10
JournalMolecular pharmaceutics
Publication statusE-pub ahead of print - 5-Aug-2020
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