Abstract
1548
Objectives P-glycoprotein (P-gp, MDR1) function in various cancer cell-lines and tumors was shown to influence 18F-FDG incorporation [1]. This suggests that P-gp function at the blood-brain barrier (BBB) may also modulate 18F-FDG brain kinetics [2].
Methods We tested the influence of two different P-gp inhibitors (valspodar and elacridar ; 5 µM), on the uptake of 18F-FDG in standardized MDCKII cells transfected with the human MDR1 gene in a glucose-free medium (D-PBS, n=4 well/condition). 99mTc-sestamibi, a known P-gp substrate was co-incubated as a positive control. Cell viability was assesed using trypan blue exclusion assay. Consequences for 18F-FDG brain kinetics were then assessed using 18F-FDG brain PET imaging (HR+ camera, 60 min acquisition) and suitable kinetic modelling (2TC model, Pmod software), including estimation of glucose consumption (CMRGlc) in 3 different baboons without or with P-gp inhibition (cyclosporine i.v infusion, 15 mg/kg/h).
Results After 60 min incubation, valspodar decreased 18F-FDG uptake whereas elacridar had no significant influence. At 120 min, both inhibitors increased 18F-FDG uptake only up to 14%. 99mTc-sestamibi uptake was systematically higher in the presence of inhibitors. Cell viability was >95 % after 120 min incubation in all tested conditions. PET analysis revealed that P-gp inhibition had no significant impact on estimated brain kinetics parameters K1, k2, k3, k4, VT and CMRGlc in the brain hemispheres and cerebellum.
Conclusions P-gp inhibitors differentially modulate 18F-FDG uptake into P-gp-overexpressing cells, possibly through variation in cell energy state. In vivo, 18F-FDG brain kinetics and estimated brain glucose metabolism were not significantly influenced by P-gp inhibition using cyclosporine. This suggests that P-gp function at the BBB is not a modulatory factor of 18F-FDG brain kinetics.
Research Support Postes d'accueil CEA/AP-HP
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