Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used C-11-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: C-11-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. C-11-metoclopramide brain kinetics were compared using PET in rats (n = 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The C-11-metoclopramide brain distribution (V-T based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. Results: C-11-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline C-11-metoclopramide brain kinetics (V-T = 2.28 +/- 0.32 and 2.04 +/- 0.19 mL.cm(-3) using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced micro dose C-11-metoclopramide V-T (7.80 +/- 1.43 mL.cm(-3)) with a 4.4-fold increase in K-1 (influx rate constant) and a 2.3-fold increase in binding potential (k(3)/k(4)) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (V-T = 6.28 +/- 0.48 mL.cm(-3)) with a 2.0-fold increase in K-1 and a 2.2-fold decrease in k(2) (efflux rate), with no significant impact on binding potential. In this situation, only parent C-11-metoclopramide could be detected in the brains of P-gp-inhibited rats. Conclusion: C-11-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain harrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx hut also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.