Improvement in the therapeutic index of cisplatin (NSC 119875) by pharmacologically induced chloruresis in the rat.

Low concentrations of chloride facilitate the conversion of cisplatin (CDDP) to cytotoxic species in aqueous solution. Low urine chloride concentrations increased CDDP-induced renal injury, while high urine chloride concentrations were protective. Sprague-Dawley rats drinking 1.2% sodium phosphate or 1.4% sodium bicarbonate and consuming low-chloride rat diet for 3 days excreted urine with a mean chloride concentration of 19.6 ± 11.3 mEq/liter. After drinking 1.0% sodium chloride with the same diet, rats which were treated with s.c. ammonium chloride (250 mg/kg for three doses) and mercaptomerin sodium (1 mg mercury per kg) on Day 3 of the experimental program developed a mean urine chloride concentration of 462 ± 172 mEq/liter. Weight, input, output, urine pH, and urine sodium concentration of the two groups did not differ. CDDP (5 mg/kg) ¡.p.produced greater renal injury in chloridedeprived rats than in control animals on normal diet and tap water and was nontoxic in the chloruresis group. In rats un dergoing chloruresis, a dose of 10 mg CDDP per kg produced quantitatively similar renal injury to that produced by 5 mg CDDP per kg in control rats. Histological renal injury correlated with CDDP dose and was greatest in the distal tubules and collecting ducts of chloride-deprived rat kidneys. High-per formance liquid chromatography fractionation of urine from catheterized rats demonstrated treatment-dependent speciation of CDDP. Urine from chloride-deprived rats contained 8.8 ±2.1% of total platinum as non-CDDP species, while urine from the chloruresis group contained only 1.5 ±0.6% as nonCDDP species (p < 0.01). The mammary carcinoma induced in female rats by i.v. N-nitrosomethylurea exhibited dose-re lated partial responses to a single dose of CDDP. There was a tumor induction rate of 100% in 120 rats with median latency of 87 days (range, 69 to 160 days) from the first of three monthly i.v. injections of 50 mg A/-nitrosomethylurea per kg. The chloruresis regimen did not significantly affect the doseresponse curve of CDDP in this model. Reduction of nephrotoxicity through altered urine platinum speciation, without loss of antitumor activity, showed that pharmacologically induced chloruresis improved the therapeutic index of CDDP.