Received for publication October 20, 2004.
Revised March 4, 2005.
Accepted for publication March 4, 2005.

Metabolic activation of Pioglitazone identified from rat and human liver microsomes and freshly isolated hepatocytes

Abstract

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 The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure.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

Key words: bioactivation, drug toxicity, glutathione conjugates, hepatocytes, mass spectrometry, metabolite identification, microsomes, peroxisome proliferator-activated receptors, reactive intermediate, reactive metabolites

This article has been cited by other articles:

				C. J. Kochansky, R. K. Rippley, K. X. Yan, H. Song, M. A. Wallace, D. Dean, A. N. Jones, K. Lasseter, J. Schwartz, S. H. Vincent, et al. Drug Metab. Dispos., September 1, 2006; 34(9): 1457 - 1461. [Abstract] [Full Text] [PDF]