PT  - JOURNAL ARTICLE
AU  - T. M. Baughman
AU  - R. A. Graham
AU  - K. Wells-Knecht
AU  - I. S. Silver
AU  - L. O. Tyler
AU  - M. Wells-Knecht
AU  - Z. Zhao
TI  - METABOLIC ACTIVATION OF PIOGLITAZONE IDENTIFIED FROM RAT AND HUMAN LIVER MICROSOMES AND FRESHLY ISOLATED HEPATOCYTES
AID  - 10.1124/dmd.104.002683
DP  - 2005 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 733--738
VI  - 33
IP  - 6
4099  - http://dmd.aspetjournals.org/content/33/6/733.short
4100  - http://dmd.aspetjournals.org/content/33/6/733.full
SO  - Drug Metab Dispos2005 Jun 01; 33
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 The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure.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