An in vitro screening system for the nephrotoxicity of various platinum coordination complexes. A cytochemical study.

Isolated rat kidney tubules were cultured in Earle's medium with and without the platinum coordination complexes. Aliquots were taken at 0, 1, 2, 3, 4, 5, 6, and 8 h and analyzed for the amount of Na+/K+-ATPase, Ca2+-ATPase, alkaline phosphatase, and acid phosphatase. Culture medium was also analyzed biochemically for the amounts of alkaline phosphatase present. There is a decrease in the various enzymes levels of the tubules after incubation in nephrotoxic analogues with a corresponding increase in the culture medium. These results compare favorably with in vivo studies. The alkaline phosphatase monitored in the rat kidney cross sections from both the normal and the drug-treated animals at 0, 3, 5, 10, and 20 days showed a correlation in the decrease of enzyme levels in the kidney with a corresponding increase in the urinary levels in both the Wistar and the Long Evans rats. The baseline levels were higher in the Long Evans rats than in the Wistar rats. After cisplatin (nephrotoxic) treatment the Long Evans rats had twice as much alkaline phosphatase in the urine at day 5 as the Wistar rats. Rats treated with cyclobutanedicarboxylatoplatinum (II) did have some alkaline phosphatase output in the urine in excess of the normal levels, but this increase was not so highly significant as to justify classifying the drug as nephrotoxic.