Abstract
Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone-based glucokinase activators revealed a facile, non-enzymatic displacement of the 4-alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Catalysis
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Chromatography, Ion Exchange
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Cytosol / drug effects
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Cytosol / enzymology
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Cytosol / metabolism
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Enzyme Activators / chemistry*
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Enzyme Activators / pharmacology*
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Glucokinase / drug effects*
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Glucokinase / metabolism*
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Glutathione / metabolism*
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Glutathione Transferase / metabolism*
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Humans
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Injections, Intravenous
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Mass Spectrometry
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Microsomes, Liver / metabolism
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Pyridones / chemistry*
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Pyridones / pharmacology*
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Rats
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Spectrophotometry, Ultraviolet
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Sulfides / chemistry*
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Sulfides / pharmacology*
Substances
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Enzyme Activators
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Pyridones
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Sulfides
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Glutathione Transferase
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Glucokinase
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Glutathione