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 [11C]metoclopramide in mice with PET. Methods PET 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. Conclusions Our 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.

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

“…In rats, co-injection of a pharmacological dose of metoclopramide (3 mg/kg, i.v) with [ 11 C]metoclopramide was shown to increase the parent fraction of [ 11 C]metoclopramide in plasma [12]. This non-linearity in radiotracer metabolism was attributed to a saturable uptake transport of [ 11 C]metoclopramide by the liver, probably mediated by organic cation transporters (OCT1/2) in rodents [26,42]. However, non-linearity was not observed in humans in whom co-injection of unlabeled metoclopramide (10 mg, i.v) did not impact the plasma kinetics of [ 11 C]metoclopramide [15].…”