Changes in tissue concentrations of 14C-doxorubicin caused by mitoxantrone, mithramycin A and vinblastine in the rat

The purpose of this study was to determine if mitoxantrone (a new antineoplastic drug) and two other anticancer agents (mithramycin A and vinblastine) could result in changes in the tissue distribution and disposition of doxorubicin in rats. Each of 16 male rats received 1 mg/kg of 14C-labeled doxorubicin on day one and received either saline, or doses of 4 mg/kg of mitoxantrone, 1.7 mg/kg of mithramycin A or 2.9 mg/kg of vinblastine on day three. All rats were sacrificed on day eight. Concentrations of radioactivity in the heart, lung, kidney and muscle were higher in the mitoxantrone treated rats than in the controls. Mithramycin A decreased the concentrations of radioactivity in liver, kidney and fatty tissues, while vinblastine increased the concentrations in heart, liver, lung, muscle and skin. In summary, mithramycin A, vinblastine and mitoxantrone caused a change in tissue concentrations of radioactivity of doxorubicin and/or its metabolites following a single I.V. dose of 14C-labeled doxorubicin in rats. This may cause elevated plasma concentrations of doxorubicin. These findings in the rat could theoretically have implications regarding doxorubicin therapy in man.