Pharmacokinetics of Doxorubicin in the Heparinized Perfusate during Isolated Hyperthermic Limb Perfusion

Abstract

Background: Hyperthermic isolated limb perfusion (HILP) is a standardized technique for treatment of malignant melanoma (MM) and soft-tissue sarcoma (SA). Doxorubicin (DOX) has proved to be effective in HILP chemotherapy. DOX levels in the perfusate can be influenced by various factors. Particularly heparin-induced precipitation and adhesion to plastics have been discussed to modify bioavailability of the drug to the treated tumor. Peripheal DOX pharmacokinetics in the perfusate were investigated to clarify if DOX levels are compromised by the artificial conditions during HILP. Data should also contribute to a further improvisation of DOX dosage during the procedure. Material and Methods: DOX pharmacokinetics were analyzed in 7 patients with MM and SA during clinical HILP of the upper/lower extremity after bolus administration of 10 or 20 mg DOX. Influence of high heparin dosage (10/25 IU/ml heparin) on DOX pharmacokinetics and adhesion to plastics was additionally evaluated during experimental perfusate recirculation without patient contact. For the detection and quantification of DOX and metabolites a high-performance liquid chromatography assay was used. Results: All patients had measurable values of DOX during the total perfusion period. Metabolites, particularly the 7-deoxyaglycones, could be detected in low concentrations. DOXol is the major metabolite of DOX in the perfusate. This implicates that an aldo-keto-reductase, which is responsible for this metabolism, must be present in peripheral tissues. Mean half-life of DOX was 27.3 + 5,6 min, mean plasma clearance was 77.8 + 41.6 ml/min. Peripheral DOX metabolism appeared to be 10-fold reduced, when compared with the systemic metabolism. i We conclude that the continuous decrease of the DOX perfusate concentration during clinical HILP seems to be mostly a function of DOX tissue absorption. This is supported by the finding that neither relevant heparin-induced DOX precipitation nor a significant loss due to adhesion to plastics was noted in the experimental setting.