Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Appenroth D, Winnefeld K, Schroter H, Rost M (1993) Beneficial effect of acetylcysteine on cisplatin nephrotoxicity in rats. J Appl Toxicol 13:189–192

    Article  PubMed  CAS  Google Scholar 

  2. Blakley BW, Cohen JI, Doolittle ND et al (2001) Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood–Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 202:1997–2001

    Google Scholar 

  3. Bodenner DL, Dedon PC, Keng PC, Katz JC, Borch RF (1986) Selective protection against cis-diamminedichloroplatinum (II)-induced toxicity in kidney, gut and bone marrow by diethyldithiocarbamate. Cancer Res 46:2751–2755

    PubMed  CAS  Google Scholar 

  4. Borgstrom L, Kagedal B, Paulsen O (1986) Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 31:217–222

    Article  PubMed  CAS  Google Scholar 

  5. Congreave IA, Berggren M, Jones TW, Dawson J, Moldeus P (1087) Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems. Biopharm Drug Dispos 8:377–386

    Article  Google Scholar 

  6. Dickey DT, Muldoon LL, Kraemer DF, Neuwelt EA (2004) Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hearing Res 193:25–30

    Article  Google Scholar 

  7. Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA (2005) Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol Exp Ther 314:1052–1058

    Article  PubMed  CAS  Google Scholar 

  8. Doolittle ND, Muldoon LL, Brummett RE et al (2001) Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 7:493–500

    PubMed  CAS  Google Scholar 

  9. Doolittle N, Lacy C, Tyson R et al (2003) Phase 1 study of N-acetylcysteine administered in the descending aorta in conjunction with carboplatin-based blood–brain barrier disruption (BBBD) in subjects with malignant brain tumors. Abstract from the Society for Neuro-Oncology Eighth Annual Meeting. Neuro-Oncology Doc. 03-1003, September 15, 2003

  10. Fishbane S, Durham JH, Marzo K et al (2004) N-acetylcysteine in the prevention of radio-contrast-induced nephropathy. J Am Soc Nephrol 15:251–260

    Article  PubMed  CAS  Google Scholar 

  11. Konstantinov S, Topashka-Ancheva M, Karaivanova M et al (1994) Antitumor, nephrotoxic and clastogenic effect of cis-DDP with DDTC or NAC. Neoplasma 41:253–258

    PubMed  CAS  Google Scholar 

  12. Korver KD, Rybak LP, Whitworth C et al (2002) Round window application of d-methionine provides complete cisplatin otoprotection. Otolaryngol Head Neck Surg 126(6):683–689

    Article  PubMed  Google Scholar 

  13. Links M, Lewis C (1999) Chemoprotectants. A review of their clinical pharmacology and therapeutic efficacy. Drugs 57:293–308

    Article  PubMed  CAS  Google Scholar 

  14. Liu R, Nair D, Ix J, Moore DH et al (2005) N-acetylcysteine for the prevention of contrast-induced nephropathy. A systematic review and meta-analysis. J General Internal Med 20:193–200

    Article  Google Scholar 

  15. Marenzi G, Assanelli E, Marana I et al (2006) N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 354:2773–2782

    Article  PubMed  CAS  Google Scholar 

  16. Muldoon LL, Pagel MA, Kroll RA et al (2000) Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res 6:309–315

    PubMed  CAS  Google Scholar 

  17. Neuwelt EA, Brummett RE, Doolittle ND et al (1998) First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther 286:77–84

    PubMed  CAS  Google Scholar 

  18. Neuwelt EA, Pagel MA, Hasler BP et al (2001) Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model. Cancer Res 61:7868–7874

    PubMed  CAS  Google Scholar 

  19. Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, Muldoon LL (2004) Bone marrow chemoprotection without compromise of chemotherapy efficacy in a rat brain tumor model. J Pharmacol Exp Ther 309:594–599

    Article  PubMed  CAS  Google Scholar 

  20. Nisar S, Feinfeld DA (2002) N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity. Ren Fail 24:529–533

    Article  PubMed  Google Scholar 

  21. Shalansky SJ, Pate GE, Levin A et al (2005) N-acetylcysteine for prevention of radiocontrast induced nephrotoxicity: the importance of dose and route of administration. Heart 91:997–999

    Article  PubMed  CAS  Google Scholar 

  22. Sheikh-Hamad D, Timmins K, Jalali Z (1994) Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment. J Am Soc Nephrol 8:1640–1644

    Google Scholar 

  23. Wu YJ, Muldoon LL, Neuwelt EA (2005) The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 312:424–431

    Article  PubMed  CAS  Google Scholar 

  24. Zagler A, Azadpour M, Mercado C, Hennekens CH (2006) N-acetylcysteine and contrast-induced nephropathy: a meta-analysis of 13 randomized trials. Am Heart J 151:140–145

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Neurology and Blood Brain Barrier Program, Oregon Health & Science University, 3181 SW Sam Jackson Parkway, L603, Portland, OR, 97239, USA

    D. Thomas Dickey, Leslie L. Muldoon, Nancy D. Doolittle & Edward A. Neuwelt

  2. Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, 97239, USA

    Leslie L. Muldoon

  3. Department of Neurosurgery, Oregon Health & Science University, Portland, OR, 97239, USA

    Edward A. Neuwelt

  4. Veterans Administration Medical Center, Portland, OR, 97239, USA

    Edward A. Neuwelt

  5. Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, 60064, USA

    Darryl R. Peterson

  6. Department of Pharmacy Practice, Oregon State University, Portland, OR, 97201-3098, USA

    Dale F. Kraemer

Authors
  1. D. Thomas Dickey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leslie L. Muldoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nancy D. Doolittle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Darryl R. Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dale F. Kraemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edward A. Neuwelt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward A. Neuwelt.

Additional information

This work was supported by a Veteran’s Administration Merit Review Grant and by NIH grants NS33618, NS34608, and NS44687 from the National Institute of Neurological Disorders and Stroke to EAN.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dickey, D.T., Muldoon, L.L., Doolittle, N.D. et al. Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models. Cancer Chemother Pharmacol 62, 235–241 (2008). https://doi.org/10.1007/s00280-007-0597-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0597-2

Keywords

Search

Navigation