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

Abstract

Purpose To investigate the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of the radiolabeled antiemetic drug [ 11 C]metoclopramide in mice with PET. Methods PET was performed in wild-type mice after administration of an intravenous microdose (<1 μg) of [ 11 C]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). [ 11 C]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 [ 11 C]Metoclopramide was highly metabolized and [ 11 C]metoclopramide-derived radioactivity was excreted into the urine. The different investigated treatments decreased (~2.5-fold) the uptake of [ 11 C]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 [ 11 C]metoclopramide. Kidney and liver uptake were moderately (~1.3-fold) reduced in Slc22a1/2 (−/−) mice. Conclusions Our results suggest a contribution of OCT1/2 to the kidney and liver uptake and of MATEs to the urinary excretion of [ 11 C]metoclopramide in mice. Cation transporters may contribute, next to variability in the activity of metabolizing enzymes, to variability in metoclopramide pharmacokinetics and side effects.

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