Tissue toxicity of doxorubicin in first and second hyperthermic isolated limb perfusion--an experimental study in...

The aim of this experimental study in dogs was to assess the tissue toxicity of doxorubicin (DOX) and the impact of dose and pharmacokinetics 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 (bw) DOX was given to all animals. In the second perfusion 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 III. At the same dosage tissue toxicity increased in comparison to the first ILP. 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 significant differences between first and second perfusion. The mean muscle tissue levels during the second ILP were lower than during the first perfusion. However, in contrast to the first perfusion, they showed a further increase after perfusate eluation. A disturbed microcirculation caused by intima proliferations in arteries and arterioles fter the first ILP may impair the removal of DOX from the intravasal and interstitial compartment and can be assumed as a reason for increased tissue toxicity. Therefore, we recommend a reduction of DOX dose in the second ILP for clinical use.