EXCRETION KINETICS OF IFOSFAMIDE SIDE-CHAIN METABOLITES IN CHILDREN ON CONTINUOUS AND SHORT-TERM INFUSION

Ifosfamide (IFO) requires metabolic activation by hydroxylation of the ring system to exert cytotoxic activity. A second metabolic pathway p roduces the cytostatically inactive metabolites 2-dechloroethyl-ifosfa mide (2D-IFO) and 3-dechloroethyl-ifosfamide (3-D-IFO) under release o f chloroacetaldehyde. This side-chain metabolism has been suggested to be involved in CNS- and renal toxicity. The total urinary excretion o f ifosfamide and its metabolites was investigated during 23 cycles in 22 children at doses ranging from 400 mg/m(2) to 3 g/m(2). The kinetic s of the excretion were compared following short-term and continuous i fosfamide infusion at a dosage of 3g/m(2). IFO and side-chain metaboli tes were analyzed by gas chromatography, the active metabolites by ind irect determination of acrolein (ACR) and IFO mustard (IFO-M) with the NBP test. 59 +/- 15% of the applied dose could be recovered in the ur ine, 23 +/- 9% as unmetabolized IFO. The main metabolite was 3-D-IFO ( 14 +/- 4%) followed by isophosphoramide mustard (IFO-M) (13 +/- 4%) an d 2-D-IFO (8 +/- 3%). Neither the total amount recovered nor the excre tion kinetics of ifosfamide and side-chain metabolites showed obvious schedule dependency. The excretion kinetics of side-chain metabolites as well as unmetabolized IFO were nearly superimposable on short-term and continuous infusion. Even after 1-hour infusion there was a lag of 3 - 6 hours until dechloroethylation became relevant. Therefore, diff erences in toxicity and efficacy cannot be explained by an influence o f the application time on the metabolic profile of ifosfamide.