TISSUE TOXICITY OF DOXORUBICIN IN FIRST AND 2ND HYPERTHERMIC ISOLATEDLIMB PERFUSION - AN EXPERIMENTAL-STUDY IN DOGS

The aim of this experimental study in dogs was to assess the tissue to xicity of doxorubicin (DOX) and the impact of dose and pharmacokinetic s after double isolated limb perfusion (ILP), Fifteen beagle dogs were assigned to three groups of five animals each. In the first ILP 0.75 mg/kg bodyweight (bm) DOX was given to all animals, In the second perf usion after an interval of 6 to 8 weeks the dosage was 0.5 mg/kg bw in group I, 0.75 mg/kg bw in group II, and 1.0 mg/kg bw in group m. At t he same dosage tissue toxicity increased in comparison to the first IL P, At the second ILP there was a dose-toxicity relationship, At a dose of 0.75 mg/kg bw pharmacokinetics of DOX in the perfusate showed no s ignificant differences between first and second perfusion, The mean mu scle tissue levels during the second ILP were lower than during the fi rst perfusion. However, in contrast to the first perfusion, they showe d a further increase after perfusate eluation, A disturbed microcircul ation caused by intima proliferations in arteries and arterioles after the first ILP may impair the removal of DOX from the intravasal and i nterstitial compartment and can be assumed as a reason for increased t issue toxicity, Therefore, we recommend a reduction of DOS dose in the second ILP for clinical use.