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Time course of the change and amelioration of nedaplatin‐induced nephrotoxicity in rats
Author(s) -
Uehara Takeki,
Tsuchiya Noriko,
Masuda Aki,
Torii Mikinori,
Nakamura Masuhisa,
Yamate Jyoji,
Maruyama Toshiyuki
Publication year - 2008
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1292
Subject(s) - nephrotoxicity , nedaplatin , excretion , necrosis , medicine , cisplatin , kidney , urinary system , toxicity , dosing , renal function , acute tubular necrosis , urology , pharmacology , chemotherapy
Nedaplatin (NDP) is a second‐generation antineoplastic platinum complex, with reduced nephrotoxicity. Two experiments were conducted to characterize the time course of changes of its nephrotoxicity and to further evaluate whether hydration is useful for amelioration of nephrotoxicity. In the first experiment, 8‐week‐old male rats treated with 6 or 9 mg kg −1 NDP at a single intravenous dose were killed 2, 4, 7 and 14 days after dosing. In the second experiment, nonhydrated (Nhyd) or hydrated (Hyd) rats, treated with a single intravenous dose of 20 mg kg −1 NDP, were killed 7 days after dosing. Besides renal function and histopathological examinations, the urinary excretion of platinum was measured. Histopathologically, NDP‐induced nephrotoxicity was initially characterized by single cell and/or focal necrosis in the epithelium of distal tubules and collecting ducts as well as proximal tubules. In the later stage, subsequent cystic dilatation and regeneration occurred in these affected tubules, but incomplete tissue repair was still observed in the kidney 14 days after dosing. However, NDP‐induced nephrotoxicity was dramatically reduced by hydration, while it had no clear effects on myelotoxicity. Measurement of urinary platinum excretion revealed that the total amount of platinum excretion was significantly higher in Hyd‐NDP rats than that in Nhyd‐NDP rats. In terms of urinary concentration, Hyd‐NDP rats showed a lower concentration compared with that in Nhyd‐NDP rats. The current results suggest that NDP has the potential risk to cause nephrotoxicity at a human therapeutic dose without hydration and that pre‐ and post‐hydration at dosing can ameliorate this nephrotoxicity. Copyright © 2007 John Wiley & Sons, Ltd.