PHARMACOKINETIC STUDIES OF MITOXANTRONE AND ONE OF ITS METABOLITES INSERUM AND URINE IN PATIENTS WITH ADVANCED BREAST-CANCER

Objective: Mitoxantrone (MTO) was administered to patients with advanc ed breast cancer either as free MTO (f-MTO) or liposomal MTO (1-MTO). The intra-and interindividual variations in serum pharmacokinetics of MTO were analysed. In addition, the excretion of MTO and its metabolit e mitoxantrone dicarboxylic acid (MTOD) in urine was determined. Metho ds: The concentration of MTO was measured by high-performance liquid c hromatography in serum over a period of 24 h and the amount of MTO and the metabolite MTOD excreted in urine over 18 h was determined. Pharm acokinetic parameters of f-MTO and 1-MTO were calculated. Results: 1-M TO had a significantly longer half-life of distribution in the deep (t hird) compartment and thus a larger area under the curve (AUC) than f- MTO. No difference was found with respect to distribution in the perip heral (second) compartment. The kinetics of MTO in serum did not signi ficantly differ between patients. In four patients repeated pharmacoki netic analyses gave superimposable results. Thus, there was no enzyme induction during therapy. By contrast, two patients with oedema had a much longer mean residence time (MRT) and AUC for MTO in serum. Despit e the altered pharmacokinetics of f-MTD and 1-MTO, no toxic adverse ef fects occurred in these two patients. Conclusions: f-MTO and 1-MTO exh ibited different distribution patterns in the deep compartment with a significantly increased half-life for 1-MTO. There is no need to monit or MTO for treatment of breast cancer patients with f-MTO, In patients with oedema, the MRT of MTO is prolonged. The clinical relevance of t his observation is as yet unclear.