title: Identification of biliary metabolites of ifosfamide using 31P magnetic resonance spectroscopy and mass spectrometry.
abstract: Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo 1H-decoupled 31P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution 31P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19+/-1.47 mM; mean+/-sd), carboxyifosfamide (2.04+/-1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05+/-2.38 mM). The unknown resonance was identified using liquid chromatography-mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW=531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of +/-drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients.
authors.affiliation: Cancer Research UK Clinical Magnetic Resonance Research Group, Royal Marsden NHS Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM25PT, UK. gsp@icr.ac.uk
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Payne
authors.forename: Andrzej S K
authors.initials: AS
authors.lastname: Dzik-Jurasz
authors.forename: Laura
authors.initials: L
authors.lastname: Mancini
authors.forename: Bernard
authors.initials: B
authors.lastname: Nutley
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism*; D001646:Bile / Q000737:chemistry*; D006168:Guinea Pigs; D007069:Ifosfamide / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide