EFFECTS OF ALPHA-TOCOPHEROL ON THE TOXICITY, DISPOSITION, AND METABOLISM OF ADRIAMYCIN IN MICE

Fourteen days after adriamycin [an antitumor agent] treatment, 15 mg/kg i.p., there was greater than 50% mortality in CDF1 mice pretreated with either olive oil or saline i.p., but only 5% mortality in animals pretreated with a single dose of .alpha.-tocopherol. However, 60 days after adriamycin, mortality was 80 .+-. 5% in all 3 groups. A single dose of .alpha.-tocopherol alone caused no deaths. Blood concentrations of [14C]adriamycin-derived radioactivity in mice pretreated with .alpha.-tocopherol or olive oil were significantly higher than those of saline controls between 3-15 min after injection. At 30 and 60 min blood concentrations of radioactivity did not differ in the 3 groups. Sixty min after adriamycin administration, concentrations of radioactivity in heart, kidney, muscle, and lung were significantly higher in the .alpha.-tocopherol and olive oil groups than in the saline controls. No differences in the metabolic profile of adriamycin were found in heart or liver, but renal concentration of adriamycin and several metabolites were higher in both the .alpha.-tocopherol and olive oil groups. In general, .alpha.-tocopherol pretreatment had only slight effect on the metabolism of adriamycin in vivo. Thus, the time-dependent efficacy of .alpha.-tocopherol in ameliorating the lethal toxicity of adriamycin in mice does not appear to result from acute changes in the distribution or metabolism of adriamycin. It appears that the effect of .alpha.-tocopherol is to delay rather than prevent the lethal toxicity of adriamycin.