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 to check access.
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.
Appenroth D, Winnefeld K, Schroter H, Rost M (1993) Beneficial effect of acetylcysteine on cisplatin nephrotoxicity in rats. J Appl Toxicol 13:189–192PubMedCrossRefGoogle Scholar
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 202:1997–2001Google Scholar
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 46:2751–2755PubMedGoogle Scholar
Borgstrom L, Kagedal B, Paulsen O (1986) Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 31:217–222PubMedCrossRefGoogle Scholar
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 8:377–386CrossRefGoogle Scholar
Dickey DT, Muldoon LL, Kraemer DF, Neuwelt EA (2004) Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hearing Res 193:25–30CrossRefGoogle Scholar
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 314:1052–1058PubMedCrossRefGoogle Scholar
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 7:493–500PubMedGoogle Scholar
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, 2003Google Scholar
Fishbane S, Durham JH, Marzo K et al (2004) N-acetylcysteine in the prevention of radio-contrast-induced nephropathy. J Am Soc Nephrol 15:251–260PubMedCrossRefGoogle Scholar
Konstantinov S, Topashka-Ancheva M, Karaivanova M et al (1994) Antitumor, nephrotoxic and clastogenic effect of cis-DDP with DDTC or NAC. Neoplasma 41:253–258PubMedGoogle Scholar
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):683–689PubMedCrossRefGoogle Scholar
Links M, Lewis C (1999) Chemoprotectants. A review of their clinical pharmacology and therapeutic efficacy. Drugs 57:293–308PubMedCrossRefGoogle Scholar
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 20:193–200CrossRefGoogle Scholar
Marenzi G, Assanelli E, Marana I et al (2006) N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 354:2773–2782PubMedCrossRefGoogle Scholar
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 6:309–315PubMedGoogle Scholar
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 286:77–84PubMedGoogle Scholar
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 61:7868–7874PubMedGoogle Scholar
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 309:594–599PubMedCrossRefGoogle Scholar
Nisar S, Feinfeld DA (2002) N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity. Ren Fail 24:529–533PubMedCrossRefGoogle Scholar
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 91:997–999PubMedCrossRefGoogle Scholar
Sheikh-Hamad D, Timmins K, Jalali Z (1994) Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment. J Am Soc Nephrol 8:1640–1644Google Scholar
Wu YJ, Muldoon LL, Neuwelt EA (2005) The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 312:424–431PubMedCrossRefGoogle Scholar
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 151:140–145PubMedCrossRefGoogle Scholar