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 produces the cytostatically inactive metabolites 2-dechloroethyl-ifosfamide (2-D-IFO) and 3-dechloroethyl-ifosfamide (3-D-IFO) under release of chloroacetaldehyde. This side-chain metabolism has been suggested to be involved in CNS- and renal toxicity. The total urinary excretion of ifosfamide and its metabolites was investigated during 23 cycles in 22 children at doses ranging from 400 mg/m2 to 3 g/m2. The kinetics of the excretion were compared following short-term and continuous ifosfamide infusion at a dosage of 3 g/m2. IFO and side-chain metabolites were analyzed by gas chromatography, the active metabolites by indirect determination of acrolein (ACR) and IFO mustard (IFO-M) with the NBP test. 59+/-15% of the applied dose could be recovered in the urine, 23+/-9% as unmetabolized IFO. The main metabolite was 3-D-IFO (14+/-4%) followed by isophosphoramide mustard (IFO-M) (13+/-4%) and 2-D-IFO (8+/-3%). Neither the total amount recovered nor the excretion 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, differences in toxicity and efficacy cannot be explained by an influence of the application time on the metabolic profile of ifosfamide.
Silies
H
H
Department of Pediatric Hematology and Oncology, University of Münster, Germany.
Blaschke
G
G
Hohenlöchter
B
B
Rossi
R
R
Jürgens
H
H
Boos
J
J
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000652:urine; D000171:Acrolein / Q000652:urine; D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use* / Q000652:urine; D002648:Child; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use* / Q000652:urine; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D010752:Phosphoramide Mustards / Q000652:urine
D018906:Antineoplastic Agents, Alkylating; D010752:Phosphoramide Mustards; C027061:isophosphamide mustard; D000171:Acrolein; C004656:chloroacetaldehyde; D000079:Acetaldehyde; D007069:Ifosfamide