A Comparative Study of Rat Urine 1H-NMR Metabolome Changes Presumably Arising from Isoproterenol-Induced Heart Necrosis Versus Clarithromycin-Induced QT Interval Prolongation

Abstract

Cardiotoxicity remains a challenging concern both in drug development and in the management of various clinical situations. There are a lot of examples of drugs withdrawn from the market or stopped during clinical trials due to unpredicted cardiac adverse events. Obviously, current conventional methods for cardiotoxicity assessment suffer from a lack of predictivity and sensitivity. Therefore, there is a need for developing new tools to better identify and characterize any cardiotoxicity that can occur during the pre-clinical and clinical phases of drug development as well as after marketing in exposed patients. In this study, isoproterenol and clarithromycin were used as prototypical cardiotoxic agents in rats in order to evaluate potential biomarkers of heart toxicity at very early stages using 1H-NMR-based metabonomics. While isoproterenol is known to cause heart necrosis, clarithromycin may induce QT interval prolongation. Heart necrosis and QT prolongation were validated by histological analysis, serum measurement of lactate dehydrogenase/creatine phosphate kinase and QTc measurement by electrocardiogram (ECG). Urine samples were collected before and repeatedly during daily exposure to the drugs for 1H-NMR based-metabonomics investigations. Specific metabolic signatures, characteristic of each tested drug, were obtained from which potential predictive biomarkers for drug-induced heart necrosis and drug-induced QT prolongation were retrieved. Isoproterenol-induced heart necrosis was characterized by higher levels of taurine, creatine, glucose and by lower levels of Krebs cycle intermediates, creatinine, betaine/trimethylamine N-oxide (TMAO), dimethylamine (DMA)/sarcosine. Clarithromycin-induced QT prolongation was characterized by higher levels of creatinine, taurine, betaine/TMAO and DMA/sarcosine and by lower levels of Krebs cycle intermediates, glucose and hippurate.