Influence of Cation Transporters (OCTs and MATEs) on the Renal and Hepatobiliary Disposition of [11C]Metoclopramide in Mice

Irene Hernández-Lozano,Michael Sauberer,Giuliano Ciarimboli,Oliver Langer,Johann Stanek,Severin Mairinger,Thomas Wanek,Thomas Filip,Nicolas Tournier

doi:10.1007/s11095-021-03002-2

Abstract

PurposeTo investigate the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of the radiolabeled antiemetic drug [11C]metoclopramide in mice with PET.MethodsPET was performed in wild-type mice after administration of an intravenous microdose (<1 μg) of [11C]metoclopramide without and with co-administration of either unlabeled metoclopramide (5 or 10 mg/kg) or the prototypical cation transporter inhibitors cimetidine (150 mg/kg) or sulpiride (25 mg/kg). [11C]Metoclopramide PET was also performed in wild-type and Slc22a1/2(−/−) mice. Radiolabeled metabolites were measured at 15 min after radiotracer injection and PET data were corrected for radiolabeled metabolites.Results[11C]Metoclopramide was highly metabolized and [11C]metoclopramide-derived radioactivity was excreted into the urine. The different investigated treatments decreased (~2.5-fold) the uptake of [11C]metoclopramide from plasma into the kidney and liver, inhibited metabolism and decreased (up to 3.8-fold) urinary excretion, which resulted in increased plasma concentrations of [11C]metoclopramide. Kidney and liver uptake were moderately (~1.3-fold) reduced in Slc22a1/2(−/−) mice.ConclusionsOur results suggest a contribution of OCT1/2 to the kidney and liver uptake and of MATEs to the urinary excretion of [11C]metoclopramide in mice. Cation transporters may contribute, next to variability in the activity of metabolizing enzymes, to variability in metoclopramide pharmacokinetics and side effects.

Highlights

Metoclopramide is a gastroprokinetic and antiemetic drug commonly prescribed for the treatment and prevention of various gastrointestinal disorders such as gastroparesis, esophageal reflux, dyspepsia, or chemotherapy-related nausea [1]
Maximum concentration of radioactivity in the kidneys and liver was reached within 5 min after [11C]metoclopramide injection and corresponded to amounts of approximately 17% and 36% of the injected dose, respectively, assuming average mouse organ volumes published in the literature [35]
The amount of radioactivity excreted into the urinary bladder at the end of the 90-min positron emission tomography (PET) scan corresponded to approximately 45% of the injected dose

Summary

Introduction

Metoclopramide is a gastroprokinetic and antiemetic drug commonly prescribed for the treatment and prevention of various gastrointestinal disorders such as gastroparesis, esophageal reflux, dyspepsia, or chemotherapy-related nausea [1]. Central side effects associated with longterm treatment with metoclopramide include tremors and Parkinson-like symptoms, which are caused by blockade of. Metoclopramide undergoes significant firstpass metabolism in the liver, resulting in highly variable oral bioavailability. One major metabolic pathway of metoclopramide is oxidation by CYP2D6 in the liver followed by conjugation [10, 11]. An NO-glucuronide has been identified as the major metoclopramide metabolite in human urine and plasma [12, 13]. Another study reported dose dependency in the uptake rate constant of metoclopramide from plasma into the rat liver, pointing to the involvement of hepatic uptake transporters in the metabolic clearance of metoclopramide [17]

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