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

Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target—in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity

Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?

Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 mu M) shortened AP duration at 90% level of repolarization (APD(90)) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 mu M) caused a significant reduction of APA and maximum velocity of depolarization (V(max)) which was accompanied by lengthening of APD(90). In single canine ventricular myocytes at concentrations >= 10 mu M R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced V(max). R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC(50) value for this inhibition was 25.2 +/- 2.7 mu M for the transient outward K(+) current (I(to)), 72.3 +/- 9.3 mu M for the rapid delayed rectifier K(+) current (I(Kr)), and 82.5 +/- 9.4 mu M for the L-type Ca(2+) current (I(Ca)) with Hill coefficients close to unity. The inward rectifier K(+) current (I(K1)) was not affected by R up to concentrations of 100 mu M. Suppression of I(to), I(Kr), and I(Ca) has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patient