Clinical trials indicate that amifostine offers protection against cisplatin-induced nephrotoxicity. It is unclear whether a direct pharmacological t on renal tubular cells is involved. We investigated the effect of amifostine pretreatment on the tubular apparatus and evaluated its nephroprotective potential. A total of 32 rats were treated by i.p. administration of 0.9% saline solution (group 1), 5 mg/kg cisplatin (group 2), 25 mg/kg amifostine (group 3), and 25 mg/kg amifostine followed by 5 mg/kg cisplatin (group 4) after 30 min. We recorded elevation of N-acetyl-beta-D-glucosaminidase (NAG) in 24 h pooled urine as a specific marker for tubular lesions, renal leakage of magnesium as an unspecific nephrotoxicity marker, and survival over a 10-day observation period. A significant (P < 0.002) increase in urinary NAG after treatment was documented only in cisplatin-treated group 2 [day 2 (mean+/-SE), 93+/-2.1 units/gram creatinine; day 4, 70.6+/-16 units/gram creatinine; normalization at day 8]. Treatment with amifostine before cisplatin administration resulted in a slight urinary NAG leakage (day 2, 2.8+/-1.8 units/gram creatinine; day 4, 13.8+/-13 units/gram creatinine; normalization at day 6). No increase in urinary enzyme levels was seen in the other groups, and there were no significant differences in urinary magnesium between all groups. Four of eight rats in the cisplatin-treated group and one of eight rats in the amifostine plus cisplatin-treated group died.