Comparative Nephrotoxicity of a Novel Platinum Compound, Cisplatin, and Carboplatin in Male Wistar Rats

The nephrotoxicity of three platinum-containing antitumor agentswas compared at doses that approximate the LDIO (cisplatin)or the LD5O (CI-973, carboplatin) doses. Male Wistar rats wereadministered 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 treatmentincreased blood urea nitrogen (4X), creatinine (3x), glucose,and fractional electrolyte excretions, and decreased creatinineclearance by Day 4. These parameters were not significantlyaltered in CI-973- and carhoplatin-treated animals. Cisplatinincreased 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 functionalchanges as a conse quence of direct nephrotoxicity: decreasesin GFR (84%), ERPF (97%), ERBF (96%), and ERTS (95%), and increasesin FF (fivefold). Functional changes, attributed to prerenaleffects of CI-973, included a decrease in ERPF (35%) and anincrease in FF (48%). No changes were seen following carboplatintreat ment. All cisplatin-treated rats had proximal tubularnecrosis in the outer stripe of the outer medulla, extendingmultifocally into inner cortical medullary rays. No renal lesionswere de tected by light or electron microscopy in the controlor Cl-973- or carboplatin-treated rats. Cisplatin produced markednephro toxicity as determined by biochemical, functional, andhisto pathologic endpoints. CI-973 and carboplatin were significantlyless nephrotoxic than cisplatin.