The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients.
PURPOSE Since doxorubicin causes cardiotoxicity, we wished to assess relative concentrations of doxorubicin and its metabolites in cardiac tissues of patients who had been treated antemortem. We also wished to determine factors that correlate with human cardiac doxorubicin and doxorubicinol concentrations. PATIENTS AND METHODS Autopsy tissues were collected from 35 patients who had received doxorubicin at any time antemortem, and were assayed by high pressure liquid chromatography. RESULTS The major species found in human autopsy cardiac tissues were doxorubicinol (median concentration 92 ng/g, range 0 to 484 ng/g), and doxorubicin (median 58 ng/g, range 0-1665 ng/g). Other doxorubicin metabolites were detected in cardiac tissues in < half the patients. Of ten organs studied, heart ranked fifth with respect to median doxorubicin concentration and ranked fourth with respect to median doxorubicinol concentration. By multiple stepwise regression analysis, factors most closely associated with cardiac doxorubicin concentrations were time from last treatment divided by dose intensity, serum total protein, albumin, and hemoglobin (negative correlations). Factors most closely associated with cardiac doxorubicinol concentrations were cumulative doxorubicin dose, total protein, hemoglobin, and uric acid (positive associations), and respiratory rate (negative association). The physiologic significance of these associations (if any) is uncertain. By paired t-tests, cardiac doxorubicin and doxorubicinol concentrations were significantly (p < 0.05) higher than concentrations in skeletal muscle and smooth muscle organs. CONCLUSIONS Overall, the results suggest that the much greater tendency to develop doxorubicin toxicity in heart than in other types of muscle may be due to a propensity of cardiac muscle to accumulate doxorubicin. The results also suggest that doxorubicinol may play a role in doxorubicin cardiac toxicity, and that doxorubicin may be gradually converted to doxorubicinol in human tissues.