title: 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 The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure.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 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.
authors.affiliation: Metabolic and Antiviral CEDD DMPK, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. todd.m.baughman@gsk.com
authors.forename: T M
authors.initials: TM
authors.lastname: Baughman
authors.forename: R A
authors.initials: RA
authors.lastname: Graham
authors.forename: K
authors.initials: K
authors.lastname: Wells-Knecht
authors.forename: I S
authors.initials: IS
authors.lastname: Silver
authors.forename: L O
authors.initials: LO
authors.lastname: Tyler
authors.forename: M
authors.initials: M
authors.lastname: Wells-Knecht
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000818:Animals; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D045162:Thiazolidinediones / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D045162:Thiazolidinediones; D000077205:Pioglitazone