title: Activated oxazaphosphorines are transported predominantly by erythrocytes.
abstract: OBJECTIVE
  Oxazaphosphorines are metabolised by a variety of pathways, one of which leads to activation and the formation of alkylating compounds. However, the transport forms conveying activated oxazaphosphorines to the tumour cell have not been fully characterised. There is increasing recognition of the importance of the erythrocyte as a carrier of compounds in the circulation, and we have recently described higher concentrations of 4-hydroxycyclophosphamide within the erythrocyte compartment compared to plasma. We have now determined the concentrations of ifosfamide and seven of its metabolites in the plasma and erythrocytes of patients receiving a six-hour intravenous infusion of ifosfamide.
  
  
  METHODS
  Red cells from five patients, receiving a total of eight cycles of ifosfamide, were separated from plasma using the MESED instrument, and analysis of red cells and plasma performed using Gas Chromatography-Mass Spectrometry (GC/MS).
  
  
  RESULTS
  The concentration of all compounds in the erythrocyte compartment was higher than or equal to those in plasma, and isophosphoramide mustard and carboxyifosfamide showed a particular affinity for the erythrocyte. The red cell fraction can contain as much as 77% of the total blood concentration of isophosphoramide mustard.
  
  
  CONCLUSIONS
  Erythrocyte associated isophosphoramide mustard is an important transport form of activated ifosfamide. Red cells may have a role in the delivery of activated oxazaphosphorines to tissues.
authors.affiliation: Department of Medical Oncology, Guy's Hospital, London, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Highley
authors.forename: D
authors.initials: D
authors.lastname: Schrijvers
authors.forename: A T
authors.initials: AT
authors.lastname: Van Oosterom
authors.forename: P G
authors.initials: PG
authors.lastname: Harper
authors.forename: G
authors.initials: G
authors.lastname: Momerency
authors.forename: K
authors.initials: K
authors.lastname: Van Cauwenberghe
authors.forename: R A
authors.initials: RA
authors.lastname: Maes
authors.forename: E A
authors.initials: EA
authors.lastname: De Bruijn
authors.forename: M B
authors.initials: MB
authors.lastname: Edelstein
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001692:Biological Transport; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007069:Ifosfamide / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide