Intrinsic electrophilicity of the 4-methylsulfonyl-2-pyridone scaffold in glucokinase activators: role of glutathione-S-transferases and in vivo quantitation of a glutathione conjugate in rats.
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.
Litchfield
John
J
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States.
Sharma
Raman
R
Atkinson
Karen
K
Filipski
Kevin J
KJ
Wright
Stephen W
SW
Pfefferkorn
Jeffrey A
JA
Tan
Beijing
B
Kosa
Rachel E
RE
Stevens
Benjamin
B
Tu
Meihua
M
Kalgutkar
Amit S
AS
D000818:Animals; D002384:Catalysis; D002852:Chromatography, Ion Exchange; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020536:Enzyme Activators / Q000737:chemistry* / Q000494:pharmacology*; D005941:Glucokinase / Q000187:drug effects* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology*
D020536:Enzyme Activators; D011728:Pyridones; D013440:Sulfides; D005982:Glutathione Transferase; D005941:Glucokinase; D005978:Glutathione