抄録
Cardio toxicity assessment by troponin analysis is uncertain in non-clinical research due to unavailability of published data. The purpose of this study was to establish analytical methods for cardiac troponin in non-human primates and to determine troponin response to drug-induced cardio-toxicity. To confirm the analytical specificity, samples were prepared by extracting protein from heart and non-heart tissues and cTnI and cTnT levels were measured by cTnI (Life Diagnostics Inc.) and cTnT (Roche) EIA systems. Method validations were performed following FDA guidelines. Approximately, 100-fold higher values of cTnI and cTnT were observed in the heart tissue origin samples compared to those from non-heart tissue origins. To determine troponin responses to drug-induced cardio toxicity, Cynomolgus Monkeys were treated with 2 mg/kg/dose (10 mg/kg at last dose) of doxorubicin up to 38 mg/kg, and troponin levels were determined on Pre-, 6 and 24 hrs Post-dosing samples, depending on animal condition. The first cTnI elevation was observed after the second doxorubicin administration in high responding animal, and the frequency of positive troponin detection increased in a dose-dependant manner. Histopathological examination confirmed doxorubicin-induced myocardial damage, microvacuolation/degeneration of myocardial fiber, in troponin positive animals. Significant correlations were observed between cTnI and common biochemical/ECG parameters. These data suggested that cardiac troponin analyses are useful tools to assess drug-induced cardio toxicity in Cynomolgus Monkeys.
