CARDIOTOXICITY STUDY OF ME2303 WITH THE INTERVAL INTRAVENOUS INJECTIONS TO RATS

Abstract

Cardiotoxic effects of ME2303 were studied upon interval intravenous administrations to rats in comparison with those of doxorubicin (ADR).
ME2303 at two dose levels of 3 and 9 mg/kg/day or ADR at a dose levels of 3 mg/kg/day was injected once a week for 3 weeks to female Sprague-Dawley rats (SPF) of 5-weeks of age. ADR depressed body weight gain, decreased food intake and increased water intake. Microscopic observation on the myocardial tissues revealed that ADR caused necrosis and cell infiltration, edema and disarrangement of myofibrils in some of ADR-treated rats. On the other hand, ME2303 showed no significant effects except that some decrease of food intake was observed at a dose level 9 mg/kg/day. No changes in left ventricular functions were observed in perfused hearts isolated from ADR- or ME2303-treated rats. However, about 133 ng/g of ADR remained in the hearts even at 1 week after the final administration whereas ME2303 or its metabolites were not detected, suggesting that ADR may cause disturbance of ventricular function and more cardio myopathy after a longer term than 1 week following the final administration.
These results suggest that the cardiotoxicity of ME2303 is weaker than that of ADR in rats.