PREVENTION OF IFOSFAMIDE NEPHROTOXICITY BY N- ACETYLCYSTEINE: CLINICAL PHARMACOKINETIC CONSIDERATIONS

Main Article Content

Nancy Chen
Katarina Aleksa
Cindy Woodland
Michael Rieder
Gideon Koren

Keywords

Ifosfamide, N-acetylcysteine, nephrotoxicity, steady state concentration, pharmacokinetics, total body clearance, clinical relevance

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 0.4mM 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.

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References

1. Schoenike SE, Dana WJ. Ifosfamide and mesna.Clin Pharm 1990;9:179- 191.
2. De Kraker J, Ifosfamide in pediatric oncology.Anticancer Drugs 1991;2:339-341.
3. Springate J, Chan K, Lu H, Davies S, Taub M.Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells. In Vitro Cell Dev Biol Anim 1999;35:314-7
4. Heney D, Wheeldon J, Rushworth P, Chapman C, Lewis IJ, Bailey CC. Progressive renal toxicity due to ifos famide. Arch Dis Child 1991;66:966-70.
5. Loebstein R, Koren G. Ifosfamide -induced Pharmacokinetics and bioavailability of reduced and oxidized N- acetylcysteine. Eur J Clin nephrotoxicity in children: critical review of predictive risk factors. Pediatrics 1998;101:E8-E12
6.Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 2003;41:190-197.
7. Loebstein R, Atanackovic G, Bishai R et al. Risk factors for long-term outcome of ifosfamide- induced nephrotoxicity in children. J Clin acetylcysteine. Clin Pha rmacokinet 1991;20:123-
8. Skinner R, Sharkey IM , Pearson AD , Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 1993;11:173-90. Ventresca GP, Lodola E. Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers. Arzneimittelforschung 1989;39:382- 6.
9. Rossi R, Pleyer J, Schafers P, Kuhn N, Kleta R, Deufel T. Development of ifosfamide-induced 24. de Wildt SN, Kearns GL, Leeder JS, van den
Anker JN. Cytochrome P450 3A: ontogeny and
nephrotoxicity: prospective follow-up in 75 -patients. Med Padiatr Oncol 1999;32:177-182

10. Chen N, Aleksa K, Woodland C, Rieder MJ,
Koren G. The Effect of N-Acetylcysteine on
Ifosfamide-Induced Nephrotoxicity. Abstract presented at 3rd Canadian Therapeutics
Congress. Canadian Journal of Clinical
Pharmacology 2006;13:e189.
11. Marzullo L. An update of N-acetylcysteine treatment for acute acetaminophen toxicity in children. Curr Opin Pediatr 2005;17:239-45.
12. Kelly GS. Clinical applications of N-
acetylcysteine. Altern Med Rev 1998;3:114- 27.
13. De Vries N, De Flora S. N- acetyl-l-cysteine. J
Cell Biochem Suppl 1993;17:270-7.
14. De Flora S, Izzotti A, D’Agostini F, Cesarone CF.
Antioxidant activity and other mechanisms of thiols involved in chemoprevention of mutation and cancer. Am J Med 1991;91:122S- 130S.
15. Borgstrom L, Kagedal B, Paulsen O.
Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 1986;31:217- 22.
16. Addis T, Watanabe CK. The volume of urine in young healthy adults on a constant diet. J. Biol. Chem 1961;27:267-272
17. Ahola T, Fellman V, Laaksonen R, Laitila J, Lapatto R, Neuvonen PJ, Raivio KO. Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants. Eur J Clin Pharmacol 1999;55:645- 50.
18. Prescott LF, Donovan JW, Jarvie DR, Proudfoot AT. The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage. Eur J Clin Pharmacol 1989;37:501- 6.
19. Jones AL, Jarvie DR, Simpson D, Hayes PC, Prescott LF. Pharmacokinetics of N- acetylcysteine are altered in patients with chronic liver disease. Aliment Pharmacol Ther 1997;11:787-91.
20. Olsson B, Johansson M, Gabrielsson J, Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N- acetylcysteine. Eur J Clin Pharmacol 1988;34:77- 82.
21. Brown M, Bjorksten A, Medved I, McKenna M. Pharmacokinetics of intravenous N-acetylcysteine in men at rest and during exercise. Eur J Clin Pharmacol 2004;60:717- 23.
22. Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet 1991;20:123-34.
23. De Caro L, Ghizzi A, Costa R, Longo A, Ventresca GP, Lodola E. Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers. Arzneimittelforschung 1989;39:382- 6.
24. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999;37:485-505.
25. Burgunder JM, Varriale A, Lauterburg BH. Effect of N -acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol 1989;36:127-31.
26. Morgan LR, Holdiness MR, Gillen LE. N-acetylcysteine: its bioavailability and interaction with ifosfamide metabolites. Semin Oncol 1983;10:56-61.

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