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Effects of Mannitol or Furosemide Diuresis on the Nephrotoxicity and Physiological Disposition of cis-Dichlorodiammineplatinum-(II) in Rats¹

Departments of Pharmacology [M. F. P., H. C. H.] and Pathology [B. C. Z.], The George Washington University Medical Center, Washington, D.C. 20037, and Department of Pharmacology, Oral Roberts University, Tulsa, Oklahoma, 74171 [H. C. H]

Although furosemide and mannitol have been reported to protect against cis-dichlorodiammineplatinum(II) (CDDP)-induced nephrotoxicity, the possibility that these diuretics might act in different ways to alter the physiological disposition) and in vivo antitumor activity of CDDP has not been adequately assessed. Therefore, we compared the effects of furosemide (12.5 mg/kg i.p. with 6.0 ml 0.9% NaCl solution) and mannitol (300 mg in 3.0 ml 0.45% NaCl solution as a 30-min i.v. infusion) on the nephrotoxicity and physiological disposition of CDDP (6 mg/kg i.v.) in male F344 rats. Serial histopathological evaluation of kidneys indicated that an approximately equivalent degree of proximal tubular necrosis occurred in rats given CDDP alone or with either furosemide or mannitol 1 to 4 days after drug administration. Thereafter, a trend developed toward less persistence of damage in the mannitol groups and progression of tubular injury in furosemide-treated rats compared to CDDP alone (5 to 10 days after drug administration). However, renal function, assessed by measurement of blood urea nitrogen, estimation of glomerular filtration rate, and p-aminohippurate clearance was partially protected in rats given either diuretic.

The administration of furosemide or mannitol did not markedly affect the triphasic plasma decay of platinum. A similar uptake of platinum into spleen and small intestine was seen at early time points (2 min to 2 hr) in groups given CDDP alone or with either diuretic. Kidney platinum content in rats receiving mannitol was similar to that of animals receiving CDDP alone. Kidneys of furosemide-treated animals contained higher levels of platinum than did kidneys of rats given CDDP alone or with mannitol at 1, 2, 24, and 96 hr after treatment. Total 24-hr urinary excretion of platinum was decreased, although not significantly, by both diuretics. Furosemide or mannitol diuresis resulted in a significant decrease in platinum concentration in 0- to 24-hr urine samples. Thus, under these conditions the partial protection of renal function observed with diuretics is not the result of increased excretion of platinum in urine, faster plasma clearance of platinum, or decreased renal levels of platinum. However, a mannitol-induced diuresis may reduce the duration of tubular necroses. It is possible that while tubular necrosis might be related to cumulative platinum uptake in the kidney, the reduction of platinum concentration in the tubular fluid caused by the diuretics might account for the protection of renal function.

¹ Supported by Grant Cl-107 from the American Cancer Society and by Grant CA-02978 from the National Cancer Institute, Department of Health, Education, and Welfare. A portion of this work was presented previously in abstract form (24).

² From a dissertation to be presented to the Graduate School of Arts and Sciences, The George Washington University, in partial fulfillment of the requirements for the Ph.D. degree.

³ To whom all correspondence should be addressed at Oral Roberts University, Tulsa, Okla. 74171.

Received 7/24/78. Accepted 1/ 3/79.

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