Metabolism of the anticancer drug ifosfamide was investigated in SpragueDawley rats. Along with four known metabolites, namely p-dechloroethylifosfamide, M-dechloroethylifosfamide, alcoifosfamide and isophosphoramide mustard, four new urinary metabolites were identified utilizing combined techniques of chemical modificationfderivatization, capillary gas chromatography/chemical ionization mass spectrometry (ammonia), deuterium-labeling/ion cluster analysis and chemical synthesis. Secondary metabolites of p-dechloroethyl and A@-dechloroethylifosfamide formed by 4hydroxylation, ie. 4-hydroxy-p-dechloroethylifosfamide and 4hydroxy-Mdechloroethylifosfamide, respectively, and their subsequent decomposition product, Ndechloroethylisophosphoramide mustard, were identified. Secondary dealkylation pathways of p-dechloroethylifosfamide and/or Mdechloroethylifosfamide were also demonstrated through characterization of p*3didechloroethyl ifosfamide. The key active metabolite of ifosfamide, 4hydroxyifosfamide, was characterized as a cyanohydrin adduct for the first time.
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