​Abstract

Rationale: PET imaging using radiolabeled high-affinity substrates of 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 ¹¹C-metoclopramide, as a model weak ABCB1 substrate, in non-human primates. 
Methods: The regional brain kinetics of a tracer dose of ¹¹C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without (n = 4) or with intravenous co-infusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h, n = 4). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution (V_T) as well as the influx (K₁) and efflux (k₂) rate constants, using a one-tissue compartment model. Modeling outcome parameters were correlated with image-derived parameters, i.e. area under the curve AUC_{0-30 min} and AUC_{30-60 min}(SUV.min) as well as the elimination slope (k_E; min^-1) from 30 to 60 min of the regional time-activity curves. 
Results: Tariquidar significantly increased the brain distribution of ¹¹C-metoclopramide (V_T = 4.3 ± 0.5 mL/cm³ and 8.7 ± 0.5 mL/cm³ for baseline and ABCB1 inhibition conditions, respectively, P<0.001), with a 1.28-fold increase in K₁ (P < 0.05) and a 1.64-fold decrease in k₂ (P < 0.001). The effect of tariquidar was homogeneous across different brain regions. The most sensitive parameters to ABCB1 inhibition were V_T (2.02-fold increase) and AUC_{30-60 min} (2.02-fold increase). V_T was significantly (P < 0.0001) correlated with AUC_{30-60 min} (r² = 0.95), AUC_{0-30 min} (r² = 0.87) and k_E (r² = 0.62). 
Conclusion: ¹¹C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and 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 non-invasively estimated from image-derived outcome parameters without the need for an arterial input function.

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