RT Journal Article
SR Electronic
T1 METABOLIC ACTIVATION OF PIOGLITAZONE IDENTIFIED FROM RAT AND HUMAN LIVER MICROSOMES AND FRESHLY ISOLATED HEPATOCYTES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 733
OP 738
DO 10.1124/dmd.104.002683
VO 33
IS 6
A1 T. M. Baughman
A1 R. A. Graham
A1 K. Wells-Knecht
A1 I. S. Silver
A1 L. O. Tyler
A1 M. Wells-Knecht
A1 Z. Zhao
YR 2005
UL http://dmd.aspetjournals.org/content/33/6/733.abstract
AB Pioglitazone is in the class of compounds known as the thiazolidinediones and is used to treat type 2 diabetes mellitus. The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure. Reactive ring-opened products of troglitazone have been identified and evidence suggests that these reactive intermediates might be a potential cause of hepatotoxicity. The present work shows that pioglitazone has a reactive ring-opened product which was trapped by glutathione and positively identified by high performance liquid chromatography with tandem mass spectrometry accurate mass measurements. The novel thiazolidinedione ring-opened products of pioglitazone were identified in rat and human liver microsomes and in freshly isolated rat but not human hepatocytes. The American Society for Pharmacology and Experimental Therapeutics