Chemical Proteomics‐Based Analysis of Off‐target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential of Cardiotoxicity

The insulin‐sensitizing drugs rosiglitazone and pioglitazone are currently the only two thiazolidinedione (TZD)‐based drugs on the market to treat type II diabetes in the U.S. Both drugs are thought to be selective for the peroxisome proliferator‐activated receptor gamma. Despite their chemical and mechanistic similarities, there are large cohort studies suggesting rosiglitazone causes congestive heart failure and peripheral edema to greater extent than pioglitazone. This study was performed to complete a mechanistic comparison between the two drugs. The common functional core between the drugs, glitazone, was used as a privileged scaffold upon which rat heart proteins were bound and eluted with glitazone, rosiglitazone, or pioglitazone. Liquid chromatography tandem mass spectrometry was used to determine the drug binding profiles. Results suggest that both drugs bind specific ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additionally, numerous proteins involved in fatty acid metabolism, glycolysis/gluconeogenesis, neuronal synaptic transduction, and energy production were detected. While there were slight differences in off‐target binding profiles between rosiglitazone and pioglitazone, there were more similarities in individual protein and pathway comparisons, suggesting similar mechanisms of action and risk profile.