Might adriamycinol contribute to adriamycin-induced cardiotoxicity

The pharmacokinetics of adriamycin (ADR) and its 13-hydroxylated-metabolite adriamycinol (ADR-ol) was investigated during treatment with ADR in rats at a dose of 2 mg/kg i.v., once a week for 3 weeks. At various times, samples of blood and cardiac and pulmonary tissues were collected to measure the amount of ADR and ADR-ol by an HPLC procedure. Periodical ECG monitoring was performed during the study; the severityof cardiac lesions was histologically evaluated at the end of treatment. During the first 180 min after ADR administration, plasma levels of ADR and ADR-ol rapidly decreased; ADR levels in cardiac and in pulmonary tissues increased between the 15th and 30th min and than decreased between the 60th and 180th min; on the contrary, ADR-ol was undetectable in either cardiac or pulmonary tissues during the first 3 hours following ADR administration. Between the 1st and 3rd weeks of treatment, plasmatic levels of ADR and ADR-ol were unchanged; in a similar way, both cardiac and pulmonary tissue levels of ADR were constant during the period of treatment. By contrast, the cardiac tissue level of ADR-ol significantly increased between the 2nd and 3rd weeks. ECG tracings showed maximal enlargement of both QRS and SαT at the end of the 3rd week. The histological examination of cardiac tissue indicated the occurrence of degenerative changes in 20% of rats at the end of the experiment. Overall results seem to indicate that ADR-ol is produced and stored in cardiac tissue during repeated ADR administration; as a consequence the cytotoxic metabolite might contribute to the cardiotoxic effect of ADR. © 1985 The Italian Pharmacological Society.