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 The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure.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 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002683.
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ABBREVIATIONS: GSH, reduced glutathione; amu, atomic mass unit(s); LC/MS, high performance liquid chromatography with tandem mass spectrometry; Q-ToF, quadrupole time of flight; HLM, human liver microsome; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; DTT, dithiothreitol; MRM, multiple reaction monitoring.
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↵1 Current address: Schering-Plough Research Institute, Kenilworth, New Jersey.
- Received October 19, 2004.
- Accepted March 4, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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