IDENTIFICATION OF NEW METABOLITES OF IFOSFAMIDE IN RAT URINE USING ION CLUSTER TECHNIQUE

Metabolism of the anticancer drug ifosfamide was investigated in Sprag ue-Dawley rats. Along with four known metabolites, namely N-2-dechloro ethylifosfamide, N-3-dechloroethylifosfamide, alcoifosfamide and isoph osphoramide mustard, four new urinary metabolites were identified util izing combined techniques of chemical modification/derivatization, cap illary gas chromatography/chemical ionization mass spectrometry (ammon ia), deuterium-labeliag/ion cluster analysis and chemical synthesis. S econdary metabolites-of N-2-dechloroethyl and N-3-dechloroethylifosfam ide formed by 4-hydroxylation, i.e. 4-hydroxy-N2-dechloroethylifosfami de and 4-hydroxy-N-3-dechloroethylifosfamide, respectively, and their subsequent decomposition product, N-dechloroethylisophosphoramide must ard, were identified. Secondary dealkylation pathways of N-2-dechloroe thylifosfamide and/or N-3-dechloroethylifosfamide were also demonstrat ed through characterization of N-2,N-3-didechloroethyl ifosfamide. The key active metabolite of ifosfamide, 4-hydroxyifosfamide, was charact erized as a cyanohydrin adduct for the first time.