Prevention of ifosfamide nephrotoxicity by N-acetylcysteine: Clinical pharmacokinetic considerations

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 0.4mM 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 0.04mM to 0.9mM and the urine concentration of NAC was 2mM. Conclusion: This suggests that the concentration chosen for in vitro studies is well within the range of clinical levels.