Tissue Distribution and Myelotoxicity of Daunomycin in Normal and Leukemic Rats: Rapid Bolus Injection versus Continuous Infusion

Abstract

The present study was designed to compare the pharmacokinetic and cytotoxic behaviour of daunomycin (DAU), administered either as a rapid bolus inj. or as a 3-hour infusion in normal and leukemic rats. DAU and its metabolite duanomycinol (DAUNOL) were determined by HPLC (Baurain et al, Cancer Chem. Pharm. 2: 37, 1979) in plasma, urine, bile and tissues. After an i.v. bolus inj. of 7.5mg/kg in BN rats the plasma level decreased biphasically (t1/2 = 18.4min and 472min). The organs showed 2 types of time/conc. curves. One type, found in lungs, liver, kidneys and heart, had an initial high drug conc. followed by a relatively rapid elimination. In the other type, found in hemopoietic tissues, the drug uptake phase lasted longer (about 1.5hr) and the elimination phase was slower. After DAU infusion a plasma steady-state level is reached in 1.5hr and high peak levels are absent. DAU infusion led to substantially lower tissue levels, including heart tissue. The experiments in which the myelotoxicity was estimated by CFU-S (colony forming units-spleen) survival (Sonneveld et al, Cancer Chem. Pharm. 5: 167, 1981) showed that bolus inj. killed twice as much CFU-S than did infusion (18& versus 34%). DAU bolus inj. or infusion in rats made leukemic by transplantable leukemia cells, led only to a slight increase in drug content in those tissues that were infiltrated by leukemic cells. About 90% of the leukemic CFU-S survived after infusion, while by bolus inj. 50% of the LCFU-S were killed. In conclusion, DAU infusion is less toxic for heart and bone marrow but DAU bolus inj. has a better therapeutic effect.