The role of biotransformation in anthracycline-induced cardiotoxicity in mice.
Anthracyclines are highly efficacious antineoplastic agents but they become cardiotoxic after repeated dosing. For the major anthracycline, doxorubicin (Dox), this toxicity is thought to be associated with the formation of the 13-dihydro metabolite. Paced mouse left atria were used to assess the cardiotoxicity of Dox, 4'-epidoxorubicin (Epi), daunorubicin (Dauno) and their major metabolites. Apart from the aglycons, all compounds (1-500 microM) reduced the contractile force. To correct for differences in cellular uptake, anthracycline concentrations were determined in the atria after 1 h of incubation. IC50 values ranged from 0.33 mumol/g for 13-dihydro-Dox to 3.5 mumol/g for Dauno. The toxicities relative to Dox, i.e., the ratio of IC50,Dox/IC50,anthracycline, ranged from 0.19 for Dauno to 2.1 for 13-dihydro-Dox (the most toxic). For Dox, Epi and Dauno, the 13-dihydro metabolite had greater toxicity than the corresponding parent compound. The pharmacokinetics of Dox and Epi in the murine heart are comparable and, thus, cannot explain the reduced cardiotoxicity of Epi. However, when pharmacokinetic data of Dox and Epi in murine heart tissue were interpreted using the relative toxicity factors, Epi would be expected to be threefold less cardiotoxic than Dox, thus providing a better correlation with in vivo data. This simple pharmacological model in combination with preclinical pharmacokinetics may contribute to the prediction of the cardiotoxic potency of new anthracyclines relative to Dox.
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
J
J
de Jong
P R
PR
Schoofs
A M
AM
Snabilié
A
A
Bast
W J
WJ
van der Vijgh
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D001711:Biotransformation; D003864:Depression, Chemical; D004317:Doxorubicin / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D006321:Heart / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009200:Myocardial Contraction / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin