Effects of prochlorperazine on experimental nephrotoxicity.

In early studies of the antitumor drug 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1nitrosourea (methyl-CCNU), animal models consistently predicted that the compound would be nephrotoxic in humans. Nephrotoxicity in cancer patients who had received methyl-CCNU was not confirmed until about 6 years after clinical trials began. We have investigated the possibility that prochlorperazine, a commonly used antiemetic, might affect the development of nephrotoxicity. Prochlorperazine (1, 2, 5, and 8 mg/kg IP on days 1-3) produced a dose-related reduction in the concentrations of plasma urea nitrogen in mice that received nephrotoxic doses of methyl-CCNU (42, 52, or 63 mg/kg IP on day 1). The frequency and severity of renal lesions evaluated histopathologically were reduced significantly as the prochlorperazine dose increased. To study further this apparent protective activity of prochlorperazine, we chose a second nephrotoxin, mercuric chloride (HgCl2, 1 mg/kg IP on day 1) and a rodent species used more commonly as a model for nephrotoxicity, the rat. Prochlorperazine (2.5 or 10 mg/kg IP on days 1-5) inhibited HgCl2-induced urinary excretion of N-acetylglucosaminidase and leucine aminopeptidase. Urinary excretion of these enzymes on day 1 reflected proximal tubular epithelial degeneration and necrosis in rats that received HgCl2 alone. The severity of HgCl2-induced renal lesions evaluated histopathologically on day 16 was significantly reduced by combination treatment with prochlorperazine. Phenothiazines have numerous pharmacologic properties that might account for this observation, and additional studies will be required to establish the mechanism of this protective effect of prochlorperazine against acute nephrotoxicity in rodents.