Identification of new metabolites of ifosfamide in rat urine using ion cluster technique

Article abstract of DOI:10.1002/jms.1190300504

Metabolism of the anticancer drug ifosfamide was investigated in Sprague-Dawley rats. Along with four known metabolites, namely N²-dechloroethylifosfamide, N³-dechloroethylifosfamide, alcoifosfamide and isophosphoramide mustard, four new urinary metabolites were identified utilizing combined techniques of chemical modification/derivatization, capillary gas chromatography/chemical ionization mass spectrometry (ammonia), deuterium-labeling/ion cluster analysis and chemical synthesis. Secondary metabolites of N²-dechloroethyl and N³-dechloroethylifosfamide formed by 4-hydroxylation, i.e. 4-hydroxy-N²-dechloroethylifosfamide and 4-hydroxy-N³-dechloroethylifosfamide, respectively, and their subsequent decomposition product, N-dechloroethylisophosphoramide mustard, were identified. Secondary dealkylation pathways of N²-dechloroethylifosfamide and/or N³-dechloroethylifosfamide were also demonstrated through characterization of N^2,3-didechloroethyl ifosfamide. The key active metabolite of ifosfamide, 4-hydroxyifosfamide, was characterized as a cyanohydrin adduct for the first time.