CARDIOTOXICITY AND COMPARATIVE PHARMACOKINETICS OF 6 ANTHRACYCLINES IN THE RABBIT

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (10) , 3530-3536
Abstract
Six anthracycline antibiotics with demonstrated antitumor activity in human or experimental tumor systems were studied. The cardiotoxic potential of these compounds was compared and the myocardial pharmacokinetics were characterized to provide a possible explanation for differences in cardiotoxicity. Groups of rabbits received i.v. injections of drug at maximally tolerated treatment doses with respect to lymphohematopoietic toxicity for periods of 11 or 16 wk, and were evaluated histopathologically for the development of myocardial damage. Following a single i.v. administration of the different anthracyclines to rabbits, the amount of parent drug and metabolites accumulating in the heart at various times was determined by high-pressure liquid chromatography and fluorometry. Adriamycin (ADR), daunorubicin (DNR) and detorubicin produced similar severe cardiomyopathy with frequent congestive heart failure at approximately equal dose levels. Three additional antibiotics, rubidazone and the N-L-leucyl derivatives of ADR and DNR (N-L-leucyl-adriamycin and N-L-leucyl-daunorubicin), produced significantly less severe lymphohematopoietic toxicity, permitting the administration of 3-3.5 times the ADR and DNR treatment doses. Chronic treatment with these anthracyclines resulted in significantly less cardiomyopathy, especially in the case of N-L-leucyl-daunorubicin and rubidazone. This reduced cardiomyopathy correlated with lower total myocardial drug accumulation, but with lower amounts of DNR or ADR accumulation in the heart. The degree of anthracycline myocardial toxicity may be directly related to the relative qualitative and quantitative accumulation of drug metabolites in the myocardium.