title: Prevention of ifosfamide nephrotoxicity by N-acetylcysteine: clinical pharmacokinetic considerations.
abstract: BACKGROUND
  Ifosfamide, which is routinely given to treat a variety of solid tumours in children, causes serious nephrotoxicity in treated children. Previous in vitro studies have shown that depletion of intracellular glutathione can enhance ifosfamide nephrotoxicity. Presently, there is no therapeutic agent that can prevent ifosfamide nephrotoxicity. We have recently shown that N-acetylcysteine (NAC) at 0.4 mM prevents ifosfamide-induced nephrotoxicity in vitro. However, this in vitro concentration of NAC needed to be compared to those used in human pharmacokinetic studies since the in vitro pharmacological effect of a compound is achieved at concentrations exceeding those used in clinical.
  
  
  OBJECTIVE
  The aim of the present study was to verify whether the in vitro concentration of NAC, which was found to protect renal cells from ifosfamide-induced damages, is comparable to the currently used clinical concentrations.
  
  
  METHODS
  A systematic literature review of all published papers reporting on the pharmacokinetics of NAC in humans was conducted.
  
  
  RESULTS
  The steady state concentrations of NAC administered intravenously to humans ranged from 0.04 mM to 0.9 mM and the urine concentration of NAC was 2 mM.
  
  
  CONCLUSIONS
  This suggests that the concentration chosen for in vitro studies is well within the range of clinical levels.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Chen
authors.forename: Katarina
authors.initials: K
authors.lastname: Aleksa
authors.forename: Cindy
authors.initials: C
authors.lastname: Woodland
authors.forename: Michael
authors.initials: M
authors.lastname: Rieder
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000111:Acetylcysteine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000633:toxicity; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D007069:Ifosfamide; D000111:Acetylcysteine