Differences in the pharmacokinetics of daunomycin in normal and leukemic rats

We compared the pharmacokinetics of daunomycin (7.5 mg/kg i.v. bolus injection) in normal and leukemic rats using a leukemia model which resembles acute myeloid leukemia in humans. Due to a more rapid decrease in plasma concentration, the area under the plasma concentration/time curve (AUC) for up to 2 h after drug injection was smaller (2.2 times) in the leukemic rats than that for normals. However, due to higher plasma levels during the drug elimination phase, the total AUC0----infinity was somewhat larger (1.3 times) in the leukemic rats. In the leukemia-infiltrated organs (spleen, liver, and lungs), significantly higher daunomycin concentrations (per gram wet weight) were found than in those obtained from normal rats. In contrast, femoral bone marrow from leukemic rats contained less daunomycin (per 10(9) nucleated cells) than did normal marrow. Quantification of the daunomycin uptake in vitro by flow cytometry showed that leukemic cells from bone marrow and spleen have an equal net drug uptake. Our data suggest that, in the presence of a high leukemic cell load, the intravenously injected daunomycin is rapidly taken up and retained by the leukemic tumor mass in, e.g., spleen, liver, and lungs, and that, as a consequence of this, the femoral marrow functions as a kind of pharmacological sanctuary.