Time course of the change and amelioration of nedaplatin-induced nephrotoxicity in rats.
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.
Uehara
Takeki
T
Developmental Research Laboratories, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan. takeki.uehara@shionogi.co.jp
Tsuchiya
Noriko
N
Masuda
Aki
A
Torii
Mikinori
M
Nakamura
Masuhisa
M
Yamate
Jyoji
J
Maruyama
Toshiyuki
T
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity* / Q000652:urine; D017209:Apoptosis / Q000187:drug effects; D001834:Body Water / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005440:Fluid Therapy / Q000379:methods; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D009944:Organoplatinum Compounds / Q000633:toxicity* / Q000652:urine; D051381:Rats; D013997:Time Factors; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C053989:nedaplatin