Positron Emission Tomography Imaging Reveals an Importance of Saturable Liver Uptake Transport for the Pharmacokinetics of Metoclopramide

Positron emission tomography (PET) imaging using [C-11] metoclopramide, a P-glycoprotein (P-gp) substrate, was used to investigate the contribution of transport processes to metoclopramide liver clearance. The liver kinetics obtained after injection of [C-11] metoclopramide were measured using PET in rats (n = 4-5) in the absence (tracer dose) and the presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using i.v. tariquidar (8 mg/kg). Corresponding [C-11] metoclopramide kinetics and metabolism in plasma (n = 3) were measured using radio-HPLC analysis. [C-11] metoclopramide exposure to the liver and plasma was described by the area under the time-activity curve (AUC) of the radioactivity kinetics in the liver and parent [C-11] metoclopramide kinetics in plasma, respectively. The pharmacologic dose of metoclopramide resulted in a similar to 2.2-fold increase in [C-11] metoclopramide AUC(plasma), while P-gp inhibition did not. AUC(liver) was lower using the pharmacologic dose (42.9 +/- 13.8 SUV.min) compared with the tracer dose (210.0 +/- 32.4 SUV.min). P-gp inhibition enhanced the liver exposure in the pharmacologic condition only (81.0 +/- 3.1 SUV.min). [C-11] metoclopramide PET imaging suggests an unpredicted role for hepatocyte uptake transporter(s) in controlling metoclopramide pharmacokinetics in addition to the known contribution of the metabolic enzymes and the P-gp.