Cardiotoxicity and comparative pharmacokinetics of six anthracyclines in the rabbit.
Six anthracycline antibiotics with demonstrated antitumor activity in human or experimental tumor systems were studied. The purpose of this investigation was to compare the cardiotoxic potential of these compounds and to characterize the myocardial pharmacokinetics in order 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 weeks 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, thus permitting the administration of 3 to 3.5 times the ADR and DNR treatment doses. Chronic treatment with these anthracyclines also 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, more importantly, with lower amounts of DNR or ADR accumulation in the heart. These findings suggest that the degree of anthracycline myocardial toxicity may be directly related to the relative qualitative and quantitative accumulation of drug metabolites in the myocardium.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity; D005260:Female; D005470:Fluorometry; D006027:Glycosides / Q000378:metabolism / Q000633:toxicity; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology; D007275:Injections, Intravenous; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009279:Naphthacenes / Q000378:metabolism / Q000633:toxicity*; D011817:Rabbits
D000903:Antibiotics, Antineoplastic; D006027:Glycosides; D009279:Naphthacenes; D004317:Doxorubicin; C017218:detorubicin; C002205:zorubicin; D003630:Daunorubicin