4.5 Article

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

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PHARMACEUTICAL RESEARCH
卷 38, 期 1, 页码 127-140

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SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-021-03002-2

关键词

[C-11]metoclopramide; multidrug and toxin extrusion proteins (MATEs); organic cation transporters (OCTs); positron emission tomography (PET)

资金

  1. Medical University of Vienna

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The study investigated the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of [C-11]metoclopramide in mice. Results showed that OCT1/2 contribute to kidney and liver uptake, while MATEs play a role in urinary excretion of the drug. Cation transporters may contribute to variability in metoclopramide pharmacokinetics and side effects.
Purpose To investigate the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of the radiolabeled antiemetic drug [C-11]metoclopramide in mice with PET. Methods PET was performed in wild-type mice after administration of an intravenous microdose (<1 mu g) of [C-11]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). [C-11]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 [C-11]Metoclopramide was highly metabolized and [C-11]metoclopramide-derived radioactivity was excreted into the urine. The different investigated treatments decreased (similar to 2.5-fold) the uptake of [C-11]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 [C-11]metoclopramide. Kidney and liver uptake were moderately (similar to 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 [C-11]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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