© 1994 Oxford University Press
research-article |
Comparative Nephrotoxicity of a Novel Platinum Compound, Cisplatin, and Carboplatin in Male Wistar Rats
Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research. Division of Warner-Lambert Company, Ann Arbor Michigan 48105 *Department of Chemistry, University of Michigan, Ann Arbor Michigan 48109
Received May 10, 1993; accepted August 6, 1993
The nephrotoxicity of three platinum-containing antitumor agents was compared at doses that approximate the LDIO (cisplatin) or the LD5O (CI-973, carboplatin) doses. Male Wistar rats were administered single iv doses of 45 mg/kg CI-973, 6.5 mg/kg cisplatin, or 65 mg/kg carboplatin and observed for 4 days. Cisplatin treatment increased blood urea nitrogen (4X), creatinine (3x), glucose, and fractional electrolyte excretions, and decreased creatinine clearance by Day 4. These parameters were not significantly altered in CI-973- and carhoplatin-treated animals. Cisplatin increased urinary excretion of LDH (six fold), GGT (twofold), and NAG (twofold); CI-973 and carbo platin increased GGT excretion (approximately twofold). Cis platin induced the following functional changes as a conse quence of direct nephrotoxicity: decreases in GFR (84%), ERPF (97%), ERBF (96%), and ERTS (95%), and increases in FF (fivefold). Functional changes, attributed to prerenal effects of CI-973, included a decrease in ERPF (35%) and an increase in FF (48%). No changes were seen following carboplatin treat ment. All cisplatin-treated rats had proximal tubular necrosis in the outer stripe of the outer medulla, extending multifocally into inner cortical medullary rays. No renal lesions were de tected by light or electron microscopy in the control or Cl-973- or carboplatin-treated rats. Cisplatin produced marked nephro toxicity as determined by biochemical, functional, and histo pathologic endpoints. CI-973 and carboplatin were significantly less nephrotoxic than cisplatin.