Effects of Mannitol Or Furosemide Diuresis on the Nephrotoxicity and Physiological Dispositionof Cis-Dichlorodiammineplatinum-(Ll) in Rats1
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(CANCER RESEARCH 39, 1269-1278, April 1979] 0008-5472/79/0039-0000$02.00 Effects of Mannitol or Furosemide Diuresis on the Nephrotoxicity and Physiological Dispositionof cis-Dichlorodiammineplatinum-(ll) in Rats1 Martin F. Pera, Jr.,2 Bernard C. Zook, and Harold C. Harder3 Departments of Pharmacology (M. F. P., H. C. H.J and Pathology (B. C. Z.J, The George Washington UniversityMedical Center, Washington, D.C. 20037, and Departmentof Pharmacology,OralRobertsUniversity,Tulsa,Oklahoma,74171(H.C. HJ ABSTRACT platinum. However, a mannitol-induced diuresis may re duce the duration of tubular necroses. It is possible that' Although furosemide and mannitol have been reported to while tubular necrosis might be related to cumulative plati protect against cis-dichlorodiammineplatinum(ll) (COOP)- num uptake in the kidney, the reduction of platinum con induced nephrotoxicity, the possibility that these diuretics centration in the tubular fluid caused by the diuretics might might act in different ways to alter the physiological dispo account for the protection of renal function. sition) and in vivo antitumor activity of COOP has not been adequately assessed. Therefore, we compared the effects INTRODUCTION of furosemide (12.5 mg/kg i.p. with 6.0 ml 0.9% NaCI solution) and mannitol (300 mg in 3.0 ml 0.45% NaCI COOP4 is an inorganic coordination complex which dis solution as a 30-mm i.v. infusion) on the nephrotoxicity and plays activity against a variety of experimental and human physiological disposition of COOP (6 mg/kg i.v.) in male neoplasms (5, 14, 15, 25). However, administration of the F344 rats. Serial histopathological evaluation of kidneys compound at therapeutic doses produces renal toxicity in indicated that an approximately equivalent degree of proxi rats, dogs, monkeys, and humans (8, 12, 14, 26, 32). mal tubular necrosis occurred in rats given COOP alone or Clinical interest in CODP has increased considerably since with either furosemide or mannitol 1 to 4 days after drug the publication of several reports indicating that induction administration. Thereafter, a trend developed toward less of diuresis prior to COOP administration to cancer patients persistence of damage in the mannitol groups and progres ameliorated the renal damage caused by the drug (3, 13, sion of tubular injury in furosemide-treated rats compared 20). However, the possibility that various diuretics might act to COOP alone (5 to 10 days after drug administration). in different ways to alter the physiological disposition, However, renal function, assessed by measurement of toxicities, and the in vivo antitumor action of CDDP has not blood urea nitrogen, estimation of glomerular filtration rate, been adequately assessed. Therefore, we have undertaken and p-aminohippurate clearance was partially protected in to investigate the toxicological, pharmacokinetic, and ther rats given either diuretic. apeutic aspects of the interaction between COOP and di The administration of furosemide or mannitol did not uretic drugs. In this paper, we evaluate the effects of markedly affect the triphasic plasma decay of platinum. A furosemide- and mannitol-induced diuresis on CDDP renal similar uptake of platinum into spleen and small intestine toxicity and physiological disposition in rats. In an accom was seen at early time points (2 mm to 2 hr) in groups given panying report (23), we describe effects of diuretics on COOP alone or with either diuretic. Kidney platinum content acute lethality, gastrointestinal and hematopoietic toxicity, in rats receiving mannitol was similar to that of animals and antitumor activity of COOP. receiving COOP alone. Kidneys of furosemide-treated ani Cvitkovic et a!. (7) found that coadministration of COOP mals contained higher levels of platinum than did kidneys with mannitol or large doses of i.v. fluids prevented the rise of rats given COOP alone or with mannitol at 1, 2, 24, and in BUN and serum creatinine which occurs following COOP 96 hr after treatment. Total 24-hr urinary excretion of administration at toxic doses in dogs. These investigators platinum was decreased, although not significantly, by both also presented some data to suggest that the level of diuretics. Furosemide or mannitol diuresis resulted in a platinum in serum after COOP was similar in dogs given significant decrease in platinum concentration in 0- to 24- mannitol or prehydration. The data provided no comparison hr urine samples. Thus, under these conditions the partial with dogs given COOP alone. The same study stated that protection of renal function observed with diuretics is not the mannitol and prehydration treatments did not alter total the result of increased excretion of platinum in urine, faster urinary clearance of platinum, although apparent increases plasma clearance of platinum, or decreased renal levels of in the recovery of platinum in urine were reported in prehydration and mannitol groups. I Supported by Grant Cl-107 from the American Cancer Society and by Grant CA-02978fromthe NationalCancerInstitute, Departmentof Health, Ward et a!. showed that the male F344 rat is sensitive to Education,and Welfare.A portion of this work was presentedpreviouslyin the nephrotoxic effects of CODP (32) and that renal dam abstractform (24). age, evidenced by elevation of BUN and necrosis of cells in 2 From a dissertation to be presented to the Graduate School of Arts and Sciences, The George Washington University, in partial fulfillment of the the proximal tubule, could be ameliorated by administration requirements for the Ph.D. degree. 3 To whom all correspondence should be addressed at Oral Roberts 4 The abbreviations used are: CDDP, cis-dichlorodiammineplatinum(lI); University. Tulsa, Okla. 74171. BUN,blood urea nitrogen; DTPA,diethylenetriaminepentaacetate;PAH,p ReceivedJuly24, 1978;acceptedJanuary3, 1979. aminohippurate; [3HJPAH,p-[glycyI-2-3H@aminohippuric acid. APRIL1979 1269 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1979 American Association for Cancer Research. M. F. Pera,Jr. et a!. of furosemide prior to the platinum drug on an acute or 5 to 6 weeks of age, the animals were separated into 4 chronic basis (33, 34). In contrast to the results of Cvitkovic treatment groups. The first group received 0.5 ml of 0.9% et al. (7)withmannitolindogs,the reportof Wardet al. (34) NaCI solution i.v. All i.v. injections were made into the mentioned unpublished work indicating that furosemide lateral tail vein using a 26-gauge x 0.5-inch needle. The treatmentofratsresultedinincreasedlevelsofplatinumin second group received COOP (6 mg/kg i.v.), the highest blood and kidney. We therefore extended the studies of dose of COOP that can be administered to these rats these groups to provide a more detailed comparison of the without producing acute lethal toxicity. The third group effects of furosemide and mannitol on the nephrotoxicity received furosemide (12.5 mg/kg i.p.) in 3.0 ml 0.9% NaCI and physiological disposition of COOP in the rat. solution 30 mm prior to COOP (6 mg/kg i.v.); 4 hr after Since data on BUN levels and renal histopathology did COOP administration, these animals were given 3.0 ml 0.9% not always agree in our experiments (24), we evaluated NaCI solution i.p. to reduce the possibility of excessive fluid additional parameters of renal function in our studies. or electrolyte derangement. The last group received man Administration of other nephrotoxic compounds, such as nitol infusions, performed after animals were lightly anes mercuric chloride and uranyl acetate, causes a decrease in thetized with pentobarbital (25 to 30 mg/kg i.p.) to facilitate glomerularfiltration (9, 11). Therefore, we used [“ln]OTPA insertion of the 27-gauge x 0.5-inch needle of an infusion blood clearance to estimate the effects of COOP alone or catheter set (EZ-Set Infusion Set; Deseret Pharmaceutical with diuretics on glomerulan filtration rate. Because other Co., Sandy, Utah) into the lateral tail vein. The rats were agents causing proximal tubular necrosis, such as paraquat placed in restraining devices with their tails secured. After or uranyl acetate, depress the organic acid secretion system the i.v. line was primed with 0.5 ml heparinized mannitol in vivo (10, 11) and because the pars recta of the proximal solution, an infusion of 10% mannitol in 0.45% NaCI solu tubule, the site of organic acid secretion (31), is apparently tion was begun at the rate of 0.10 mI/mm using a Harvard most sensitive to COOP-induced damage in the rat (32), we Infusion Pump Model 975 (Harvard Apparatus Co. Inc., measured clearance of PAH as a further indication of Millis, Mass.). Following 25 mm of mannitol infusion, COOP nephron function. In other experiments, we studied the (6 mg/kg) was injected as a bolus into the freely flowing i.v. effects of furosemide and mannitol on the physiological line. The infusion was continued for an additional 5 mm so disposition of COOP by monitoring plasma, urine, kidney, that rats received a total of 300 mg mannitol in 3.0 ml 0.45% intestine, and spleen levels of platinum, the active center of NaCI solution. COOP, at various time points. Through these measure Collectionof PlasmaTissue, and Urine Samples. Four ments, we hoped to determine if diuretics were causing series of experiments were performed to study BUN levels, major alterations in the disposition of COOP, a compound kidney pathology, and platinum disposition. In Experiment which is eliminated predominantly by the kidneys. 1, ratsin each treatmentgroup were housed in plastic cages. Blood samples (150 to 200 @tI)wereobtained from MATERiALS AND METHODS the netroorbital sinus using hepaninized Natelson capillary tubes 1 and 2 hr after COOP administration; these samples Chemicals. COOPwas obtainedfrom the Drug Liaison were spun down in a Bninkmann Model 3200 Micro Centri and Distribution Section, Division of Cancer Treatment, fuge (Brinkmann Instruments, Inc., Westbury, N. V.) to National Cancer Institute, NIH, Bethesda, Md.