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Monthly Dinner Meeting
Tuesday, February 8, 2011
“Identification of Novel Metoclopramide Metabolites in Humans:
in vitro
and in vivo studies”
Upendra A. Argikar, Ph.D.1
and Swati Nagar, Ph.D.2
1Novartis
Institutes for Biomedical Research, Inc. Cambridge MA
2Department
of Pharmaceutical Sciences, Temple University, Philadelphia PA
Social mixer begins at
5:45 pm in Frick Laboratory, Taylor Commons, Princeton
University with presentation at 6:30 pm in the Auditorium
followed by dinner in the Commons.
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. Our focus was to better understand MCP metabolism
in humans. To this end, 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 diphosphoglucuronosyl transferases (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. Several novel metabolites of MCP were identified
in human urine. These were corroborated with in vitro
studies. Further, additional novel metabolites were
identified in vitro. These results will be discussed in
detail.
Biographical Sketches of Speakers
Upendra A. Argikar
is a Research
Investigator in the Metabolism and Pharmacokinetics
Department at the Novartis Institutes for Biomedical
Research, Inc. (NIBRI), in Cambridge, MA. He received a B.
Pharmaceutical Sciences degree in 2002 from the University
of Mumbai in India and a Ph.D. in 2006 in medicinal
chemistry from the University of Minnesota, Twin Cities. He
joined NIBRI in 2006, and his primary research focus is drug
biotransformation and pharmacokinetics. His research
interests also include conjugative metabolism by human
uridine glucuronosyl transferase enzymes (UGTs). He has
numerous publications in this area, including three book
chapters on UGTs and conjugative metabolism, including two
chapters in an internationally recognized text-book series
‘Drugs and the Pharmaceutical Sciences’, and presentations
at conferences and as an invited speaker at several national
and international institutions.
Swati Nagar
is currently
Assistant Professor at Temple University School of Pharmacy,
Department of Pharmaceutical Sciences. She earned her Ph.D.
in Pharmacokinetics at the University of Minnesota in 2003
and had a postdoctoral fellowship in 2005 focused on
pharmacogenetics of ‘phase II’ enzymes in the laboratory of
Dr. Rebecca Blanchard at Fox Chase Cancer Center. Swati’s
research now focuses on ‘phase II’ xenobiotic conjugation,
specifically glucuronidation and sulfation. Her lab is
interested in enzyme kinetics, enzyme induction/inhibition,
reaction phenotyping, and genotype-phentoype correlations of
reactions catalyzed by uridine diphosphoglucuronosyl
transferases (UGTs) and sulfotransferases (SULTs). In
addition to in vitro xenobiotic metabolism, her lab focuses
on pre-clinical pharmacokinetics with a special focus on
metabolism and metabolite kinetics.
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