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Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 2, pp 235–241 | Cite as

Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models

  • D. Thomas Dickey
  • Leslie L. Muldoon
  • Nancy D. Doolittle
  • Darryl R. Peterson
  • Dale F. Kraemer
  • Edward A. NeuweltEmail author
Original Article

Abstract

Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50–1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 ± 8.2 and 123.3 ± 8.2, respectively) or CR (2.3 ± 0.38 and 1.77 ± 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 ± 6.8, CR 0.47 ± 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are affected by the dose and route of administration.

Keywords

N-acetylcysteine Cisplatin Chemoprotection Route Rats 

Notes

Acknowledgments

Expert technical assistance by Michael Pagel and Asad Khan in the total NAC analysis was greatly appreciated.

Conflict of interest statement Drs. Neuwelt and Muldoon, Oregon Health & Science University (OHSU), Portland Veterans Affairs Medical Center (PVAMC) and the Department of Veterans Affairs have a significant financial interest in Adherex, a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest was reviewed and managed by the OHSU Integrity Program Oversight Council and the PVAMC Conflict of Interest in Research Committee. Dr. Neuwelt has divested his financial interests in Adherex.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • D. Thomas Dickey
    • 1
  • Leslie L. Muldoon
    • 1
    • 2
  • Nancy D. Doolittle
    • 1
  • Darryl R. Peterson
    • 5
  • Dale F. Kraemer
    • 6
  • Edward A. Neuwelt
    • 1
    • 3
    • 4
    Email author
  1. 1.Department of Neurology and Blood Brain Barrier ProgramOregon Health & Science UniversityPortlandUSA
  2. 2.Department of Cell and Developmental BiologyOregon Health & Science UniversityPortlandUSA
  3. 3.Department of NeurosurgeryOregon Health & Science UniversityPortlandUSA
  4. 4.Veterans Administration Medical CenterPortlandUSA
  5. 5.Department of Physiology and BiophysicsRosalind Franklin University of Medicine and Science, The Chicago Medical SchoolNorth ChicagoUSA
  6. 6.Department of Pharmacy PracticeOregon State UniversityPortlandUSA

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