Increasing the accumulation of daunorubicin in human leukemic cells by prolonging the infusion time

Eight patients with acute nonlymphoblastic leukemia were treated with a combination of daunorubicin (1.5 mg/kg body weight) and cytosine arabinoside. The infusion time of daunorubicin was varied from 10 min to 24 h. One patient received the drug during 24 h in one treatment course and during 10 min in the subsequent course. The concentrations of daunorubicin and its main metabolite, daunorubicinol, were monitored simultaneously in plasma and in leukemic cells using high performance liquid chromatography. Infusion during 24 h gave a peak plasma concentration of daunorubicin that was less than one tenth of that observed after infusion for 10 min, while the areas under the plasma concentration vs time curves were similar. In contrast, prolonging the infusion time increased the area under the cellular concentration vs time curve from a mean of 3.3 nmol x h/mg cell protein for infusions less than one hour to 13.7 and 17.0 nmol x h/mg cell protein in two patients who received the same dose as a 24-h infusion. The duration of the infusion did not influence the intracellular levels of daunorubicinol. We conclude that the infusion times appear to affect the concentration of daunorubicin in the leukemic cells and may be important for the therapeutic effects of daunorubicin.