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Identification of novel metoclopramide metabolites in humans: in vitro and in vivo studies

Argikar, Upendra and Gomez, Javier and Ung, Din and Parkman, Henry and Nagar, Swati (2010) Identification of novel metoclopramide metabolites in humans: in vitro and in vivo studies. Drug Metabolism and Disposition.

Abstract

Metoclopramide (MCP) is frequently used to treat gastroparesis patients. Previous studies have documented MCP metabolism, but systematic structural identification of metabolites has not been performed. This study aims to better understand MCP metabolism in humans. For examination of in vivo metabolism, a single oral 20 mg MCP dose was administered to 8 healthy male volunteers, followed by complete urine collection over 24 hours. In vitro incubations were carried out in human liver microsomes (HLM) to characterize metabolism via cytochromes P450 (CYPs) and uridine diphosphoglucuronosyltransferases (UGTs), and in human liver cytosol (HLC) for metabolism via sulfotransferases (SULTs). Urine and sub-cellular incubations were analyzed for MCP metabolites on a Thermo Orbitrap® mass spectrometer with accurate mass measurement capability. Five MCP metabolites were detected in vivo, and 5 additional metabolites were detected in vitro. The 5 metabolites of MCP identified both in vitro and in vivo were: an N-O-glucuronide (M1), an N-sulfate (M2), a des-ethyl metabolite (M3), a hydroxylated metabolite (M4), and an oxidative de-aminated metabolite (M5). To our knowledge, metabolites M1 and M4 have not been previously reported. M2 urinary levels varied 22-fold and M3 levels varied 16-fold among 8 subjects. In vitro studies in HLMs revealed following additional metabolites - two ether glucuronides (M6, M8) possibly on the phenyl ring post-oxidation, an N-glucuronide (M7), a carbamic acid (M9), and a nitroso metabolite (M10). Metabolites M6 – M10 have not been reported previously. In conclusion, this study describes the identification of MCP metabolites in vivo and in vitro, in humans.

Item Type: Article
Keywords: UGT, metabolite identification, metoclopramide
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/2501

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