Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models.
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.
Dickey
D Thomas
DT
Department of Neurology and Blood Brain Barrier Program, Oregon Health & Science University, 3181 SW Sam Jackson Parkway, L603, Portland, OR, 97239, USA.
Muldoon
Leslie L
LL
Doolittle
Nancy D
ND
Peterson
Darryl R
DR
Kraemer
Dale F
DF
Neuwelt
Edward A
EA
D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007269:Injections, Intra-Arterial; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007677:Kidney Function Tests; D051381:Rats; D020318:Rats, Long-Evans
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D002945:Cisplatin; D000111:Acetylcysteine