Control of nephrotoxicity in the rat during repeated cis‐platinum treatments

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Abstract
The nephrotoxicity of cis‐platinum (CDDP) in the rat can be controlled throughout a series of weekly administrations of CDDP (each of 5 mg kg−1, i.v.) for at least three weeks by a combination of protective measures involving pretreatment with dithiocarbamates and diuretics and the administration of appropriate dithiocarbamates given 1h after the CDDP. The use of dithiocarbamates with polar substitutents is effective in removing both renal and hepatic deposits of platinum from rats subsequent to its administration and in this respect these compounds are significantly superior to meso‐2,3‐dimercaptosuccinic acid (DMSA) in the rate at which platinum is removed and in the amounts removed. The most effective of the dithiocarbamates remove ca. 70% of the platinum from the kidneys and the liver; the least effective remove ca. 50% of the platinum from these organs when given at a level of 1.57 mmol kg−1 i.p. for 6 days subsequent to the administration of CDDP. Acetazolamide was shown to be much less effective in preventing renal damage than the dithiocarbamates and was not effective in reducing renal or hepatic levels of platinum. Pretreatment with sodium diethyldithiocarbamate 12h prior to the administration of the CDDP was more effective in preventing renal damage than the administration of this compound 30 min before the cis‐platinum. Several dithiocarbamates are found to be superior to sodium diethyldithiocarbamate in reducing renal platinum burdens of rats given CDDP at the level of 6 mg kg−1, and dose—response curves for the removal of renal and hepatic platinum were determined for sodium N‐methyl‐D‐glucamine dithiocarbamate (NaG). The use of dithiocarbamates, other than sodium diethyldithiocarbamate, to control the nephrotoxicity of CDDP may possess some advantages in the clinic.