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Paclitaxel and Docetaxel Enhance the Metabolism of Doxorubicin to Toxic Species in Human Myocardium¹

Department of Drug Sciences, G. D’Annunzio University School of Pharmacy, 66013 Chieti [G. M., P. M.]; Institute of Pharmacology, Catholic University School of Medicine, 00168 Rome [A. S., S. L.]; Department of Cardiac Surgery, G. D’Annunzio University School of Medicine, 66100 Chieti [A. M. C., G. T.]; Division of Medical Oncology, Istituto Nazionale Tumori, 20133 Milan [L. G.], Italy

Doxorubicin cardiotoxicity is a multifactorial process in which the alcohol metabolite doxorubicinol mediates the transition from reversible to irreversible damage. We investigated whether the tubulin-active taxane paclitaxel increases conversion of doxorubicin to doxorubicinol, thus explaining the high incidence of congestive heart failure when doxorubicin is used with paclitaxel. Specimens of human myocardium from patients undergoing bypass surgery were processed to obtain cytosolic fractions in which doxorubicin was converted to doxorubicinol by NADPH-dependent aldo/keto or carbonyl reductases. In this model, clinically relevant concentrations of paclitaxel (1–2.5 µM) increased doxorubicinol formation by mechanisms consistent with allosteric modulation of the reductases. Stimulation was observed over a broad range of basal enzymatic activity, and was accompanied by a similar pattern of enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity. The closely related analogue docetaxel had effects similar to paclitaxel, but increased doxorubicinol formation over a narrower range of enzymatic activity. The unrelated tubulin-active alkaloid vinorelbine had no effect. These results demonstrate that taxanes have a unique potential for enhancing doxorubicin metabolism to toxic species in human myocardium. The effects on doxorubicinol formation provide clues to explain the clinical pattern of doxorubicin-paclitaxel cardiotoxicity and also caution against the potential toxicity of combining docetaxel with high cumulative doses of doxorubicin.

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