title: A new approach to the study of ifosfamide metabolism by the analysis of human body fluids with 31P nuclear magnetic resonance spectroscopy.
abstract: [31P] nuclear magnetic resonance spectroscopy was used to analyze body fluids from patients treated with ifosfamide (IF). This technique, which requires no labeled drug, allows a direct study of the biological sample with no need for extraction or derivatization and a simultaneous detection and quantification of all the different phosphorated metabolites in a single analysis. In urine, isophosphoramide mustard was detected in addition to the already known human urinary compounds [i.e., unchanged IF, carboxyifosfamide, 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, ketoifosfamide]. 2,3-Didechloroethylifosfamide itself was not found, but two of its degradation compounds were detected, thus showing a minor route of didechloroethylation of IF in humans. Several other signals corresponding to unknown metabolites or to degradation compounds of IF metabolites were observed. None of them corresponded to IF-activated metabolites (4-hydroxyifosfamide, aldoifosfamide) or to conjugates of IF or its metabolites with mesna. The urinary excretion of IF and metabolites over 24 h amounted to 39 to 50% of the injected dose. Unmetabolized IF was the major compound in 0- to 8-h and 8- to 16-h fractions. 2-Dechloroethylifosfamide and 3-dechloroethylifosfamide were the main metabolites detected in each 8-h fraction. The two unknown compounds at 19.16 ppm and 16.06 ppm represented a non-negligible fraction of the excretion, above that of carboxyifosfamide. Only unchanged IF could be detected in plasma samples. Unmetabolized IF and 3-dechloroethylifosfamide were found in a cerebrospinal fluid sample. Neither IF nor IF metabolites could be observed in the corresponding plasma sample. This indicates a long persistence of these compounds in cerebrospinal fluid.
authors.affiliation: IMRCP Laboratory, Université Paul Sabatier Toulouse, France.
authors.forename: R
authors.initials: R
authors.lastname: Martino
authors.forename: F
authors.initials: F
authors.lastname: Crasnier
authors.forename: N
authors.initials: N
authors.lastname: Chouini-Lalanne
authors.forename: V
authors.initials: V
authors.lastname: Gilard
authors.forename: U
authors.initials: U
authors.lastname: Niemeyer
authors.forename: M
authors.initials: M
authors.lastname: De Forni
authors.forename: M C
authors.initials: MC
authors.lastname: Malet-Martino
mesh_terms: D001826:Body Fluids / Q000737:chemistry*; D006801:Humans; D007069:Ifosfamide / Q000032:analysis / Q000378:metabolism* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D012509:Sarcoma / Q000378:metabolism; D012983:Soft Tissue Neoplasms / Q000378:metabolism
chemical_list: D007069:Ifosfamide