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Drug Metabolism and Disposition Fast Forward
First published on March 11, 2005; DOI: 10.1124/dmd.104.002683

0090-9556/05/3306-733-738$20.00
DMD 33:733-738, 2005

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METABOLIC ACTIVATION OF PIOGLITAZONE IDENTIFIED FROM RAT AND HUMAN LIVER MICROSOMES AND FRESHLY ISOLATED HEPATOCYTES

T. M. Baughman, R. A. Graham, K. Wells-Knecht1, I. S. Silver, L. O. Tyler, M. Wells-Knecht, and Z. Zhao

Metabolic and Antiviral CEDD DMPK, GlaxoSmithKline, Research Triangle Park, North Carolina (T.M.B., R.A.G., K.W.-K., I.S.S., L.O.T., M.W.-K.); and Amgen, Inc., Cambridge, Massachusetts (Z.Z.)

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 The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure.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.

Address correspondence to: Todd M. Baughman, GlaxoSmithKline, Inc., MV CEDD DMPK, 5 Moore Drive, Research Triangle Park, NC 27709. E-mail: todd.m.baughman{at}gsk.com




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