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

Abstract

Positron emission tomography (PET) imaging using [11C]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 [11C]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 [11C]metoclopramide kinetics and metabolism in plasma (n=3) were measured using radio-HPLC analysis. [11C]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 [11C]metoclopramide kinetics in plasma, respectively. The pharmacologic dose of metoclopramide resulted in a ∼2.2-fold increase in [11C]metoclopramide AUCplasma, while P-gp inhibition did not. AUCliver 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). [11C]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.

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate 11C-Metoclopramide Assessed with PET Imaging in Humans

“…11 C-metoclopramide was prepared from 11 C-carbon dioxide and O-desmethyl metoclopramide (good manufacturing practice quality; ABX) following a previously published procedure (20). For intravenous injection, 11 C-metoclopramide was formulated in phosphate-buffered saline solution containing 8.6% (v/v) ethanol.…”

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

“…Tariquidar solutions for intravenous injection (3 mg/mL) were freshly prepared on the day of the experiment by dissolving tariquidar dimesylate 2.35 H 2 O (;300 mg) in a 5% (w/v) glucose solution (50 mL) followed by dilution with sterile water (50 mL). Ready-to-inject 11 Cmetoclopramide (4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-11 Cmethoxybenzamide) more than 99% radiochemically pure was prepared and controlled as previously described (19,21).…”

“…For analysis, samples were thawed at room temperature. The internal standard solution (diluted with water to a concentration of 60 mgÁmL 21 [100 mL]) and water containing 4% hydrochloric acid (v/v, 500 mL) were added to the plasma sample (600 mL). After being stirred in a vortex mixer, 1 mL of this mixture was deposited on a cation-exchange solid-phase extraction cartridge (MCX, 30 mg, Oasis; Waters) that had been preconditioned with 1 mL of methanol and 1 mL of water.…”

Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers

“…Liver imaging estimates concentrations that should be high enough for drugs targeting hepatocytes but low enough to avoid cell injury when the target is extrahepatic (Chu et al, 2013;Dollery, 2013;Guo et al, 2018). Pharmacokinetic models of liver images acquired over time estimate transfer rates and CLs between two compartments of the liver, as well as liver area under the curve (AUC) (Ali et al, 2018;Bauer et al, 2018a;Caillé et al, 2018;Kaneko et al, 2018;Leporq et al, 2018). Some of these studies suggest that liver concentrations might be more altered than systemic concentrations when inhibitors such as rifampicin (RIF) are concomitantly substrates of uptake transporters and decrease bile excretion rates (v bile ) Unadkat, 2016, 2018;Benet et al, 2018a;Kaneko et al, 2018).…”