P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of C-11-Metoclopramide Across the Blood-Brain Barrier: A PET Study on Nonhuman Primates

PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of C-11-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. Methods: The regional brain kinetics of a tracer dose of C-11-metoclopramide (298 +/- 44 MBq) were assessed in baboons using PET without (n = 4) or with (n = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution (V-T), as well as the influx (K-1) and efflux (k(2)) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV center dot min) and the elimination slope (k(E); min(-1)) from 30 to 60 min. Results: Tariquidar significantly increased the brain distribution of C-11-metoclopramide (V-T 5 4.3 +/- 0.5 mL/cm(3) and 8.7 +/- 0.5 mL/cm(3) for baseline and ABCB1 inhibition conditions, respectively, P < 0.001), with a 1.28-fold increase in K-1 (P < 0.05) and a 1.64-fold decrease in k(2) (P < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were V-T (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). V-T correlated significantly (P < 0.0001) with AUC from 30 to 60 min (r(2) = 0.95), with AUC from 0 to 30 min (r(2) = 0.87), and with k(E) (r(2) = 0.62). Conclusion: C-11-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.