Time- and dose-related modifications in cardiac function in rats after single intravenous doses of epirubicin.

Time-related changes in cardiac output have been studied in rats after the intravenous administration of a range of single doses of epirubicin. There was an initial decline in cardiac function in the first 4-12 weeks after drug treatment at a rate that appeared to be dose-related. After 12 weeks, an average cardiac output of approximately 70%, relative to control values, was maintained in animals that survived until the end of the study. This effect was independent of the drug dose, reflecting the death of animals in the higher dose groups. The incidence of drug-induced cardiotoxic deaths, the majority of which (approximately 62%) occurred within the first 12 weeks, was dose-related, and suggested a LD50 for cardiac-related mortality of 5.48 +/- 0.39 mg/kg. There appeared to be a relationship between the reduction in cardiac output at 12 weeks and the probability of a further deterioration in function. Animals showing a greater than 40% reduction in cardiac output at 12 weeks accounted for greater than 90% of all the additional deaths between 12 and 20 weeks. Rats showing a less than 40% reduction in cardiac output at 12 weeks had a very high probability of surviving without clinical signs, although with a persistently depressed cardiac function. These findings are similar to the trends demonstrated in the sparse clinical data and this supports the view that the present simple animal model is suitable for the investigation of cardiotoxicity after the administration of cardiotoxic cytotoxic drugs.