Tissue distribution and myelotoxicity of daunomycin in the rat: rapid bolus injection vs continuous infusion

The pharmacokinetic and cytotoxic behaviour of daunomycin in rats (7.5 mg/kg) when administered as an i.v. bolus injection were compared with those of a 3-hr infusion. After an i.v. bolus injection, the plasma drug levels decreased triphasically (t1/2 alpha = 0.8 min, t1/2 beta = 29.6 min and t1/2 gamma = 9.9 hr). The organs showed two types of concentration/time curves. One was found in the lungs, liver, kidneys and heart and had an initial high drug concentration followed by a relatively rapid elimination. The other was shown by the hemopoietic tissues (spleen and bone marrow): the drug uptake phase lasted longer (about 1.5 hr) and the elimination was slower. In general, daunomycin infusion led to substantially lower plasma and tissue levels, including in the heart, liver and kidneys. Again the hemopoietic tissues behaved in a different way: in spleen and bone marrow almost equal drug levels were obtained after daunomycin infusion as compared to a bolus injection. The myelotoxicity after daunomycin treatment was assessed by CFU-S (colony forming units-spleen) survival: the bolus injection killed as many CFU-S as did infusion (mean +/- S.D.: 11.8 +/- 5.3 CFU-S survival versus mean +/- S.D.: 13.5 +/- 2.4). Thus, it can be predicted that daunomycin infusion will lead to less cardiotoxicity but to an equal bone marrow suppression.