A functional assessment of the relative cardiotoxicity of adriamycin and epirubicin in the rat.
The cardiotoxicity of the two anthracyclines, adriamycin and epirubicin, were studied in 14-week-old Sprague-Dawley rats after the intravenous administration of single doses of 1-4 mg/kg of adriamycin and 2-6 mg/kg of epirubicin. These doses of the two drugs were well tolerated with little acute toxicity. Acute toxicity was characterised by a transient reduction in body weight with recovery within 14 days. The cardiac output of the rats was measured at 4-weekly intervals, for up to 20 weeks, using an external counting technique with the radioactive tracer, 99mTc. The time-related changes in cardiac function in the rat after adriamycin and epirubicin were similar. The time course of the changes in cardiac output were biphasic. There was an initial phase of rapid decline in cardiac output in the first 12 weeks (phase I) and a second phase of persistent depression in cardiac function (phase II) after 12 weeks. The late progression of anthracycline-induced cardiotoxicity could be predicted from the measurements of cardiac output at 12 weeks. The relative cardiotoxicity of adriamycin and epirubicin was evaluated from the reductions in cardiac output and from the incidence of deaths related to cardiotoxicity. Both methods of evaluation showed that adriamycin was approximately twice as cardiotoxic as epirubicin. This relationship was independent both of the dose level of drugs used and of the damage level used for the evaluation. Dose-response curves were steeper for adriamycin than for epirubicin. The present findings agree with the somewhat limited clinical data suggesting that the present rat model is highly predictive and clinically relevant.
CRC Normal Tissue Radiobiology Research Group, University of Oxford, Churchill Hospital, U.K.
T K
TK
Yeung
R H
RH
Simmonds
J W
JW
Hopewell
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D015251:Epirubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D007928:Lethal Dose 50; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D015251:Epirubicin; D004317:Doxorubicin