Studies on nephrotoxicity following a single and repeated administration of cis-diamminedichloroplatinum (CDDP) in rats.

Mizushima, Yutaka; Nagahama, Hirotoku; Yokoyama, Akihito; Morikage, Toshihiko; Yano, Saburo

doi:10.1620/tjem.151.129

Cited by 11 publications

(12 citation statements)

References 9 publications

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“…Indeed, in cisplatin-treated rats, signs of necrosis were more frequently observed in proximal tubules as well as a vacuolization and locally sloughed cells in some lumen of distal tubules. These morphological changes are in agreement with the findings of Mizushima et al [27] who showed a degenerative necrosis of the renal epithelium in rats following a single and repeated administration of cisplatin. Other degenerative changes observed in cis platin-treated rats concerned mitochondrial alterations and reduction of rough endoplasmic reticulum [28].…”

Section: Discussionsupporting

confidence: 92%

Cisplatin Nephrotoxicity in Cadmium-Pretreated Rats

Bompart¹,

Orfila²,

Manuel³

1991

Nephron

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Treatment of rats with cisplatin or with cisplatin after chronic pre-exposure to cadmium induced a decrease in kidney cytochrome P-450 and glutathione levels, and in glutathione peroxidase and reductase activities. Furthermore, cadmium and cisplatin enhanced lipid peroxidation, oxidized glutathione and N-glucuronyl transferase activity. Glutathione S-transferase (substrate: 1-chloro-2,4-dinitrobenzene) was increased and decreased by cadmium and cisplatin respectively. On morphological observation, cadmium nephrotoxicity was characterized by tubular proximal damage with mitochondrial and lysosomal changes and a widespread vesiculation of tubular cells. A marked focal tubular necrosis associated with cyst formation was observed in cisplatin nephrotoxicity. On the basis of the measured biochemical, functional and histological parameters, it is concluded that cadmium pretreatment did not potentiate the nephrotoxic effect of cisplatin.

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Section: Discussionsupporting

confidence: 92%

Cisplatin Nephrotoxicity in Cadmium-Pretreated Rats

Bompart¹,

Orfila²,

Manuel³

1991

Nephron

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“…Nephrotoxic effect of CDDP Nephrotoxicity from CDDP is well known (Mizushima et al 1987: Meyer and Madias. 1994: Leibbrandt et al 1995.…”

Section: Tumoursmentioning

confidence: 99%

Diuretic response to cyclophosphamide in rats bearing a matrix metalloproteinase-9-producing tumour

Mizushima

Sassa²,

Hamazaki³

et al. 1998

Br J Cancer

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Summary When cyclophosphamide (CY) (100-120 mg kg-') was administered intravenously (i.v.) to normal F-344 rats, oliguria occurred over the 5-day observation period. Conversely, in rats bearing matrix metalloproteinase-9 (MMP-9) producing 1 3762NF mammary adenocarcinoma (MTLn3 clone), polyuria occurred chiefly during the first 24 h after CY treatment. In parallel with urine volume, a decrease in the urinary excretion of Nacetyl-beta-D-glucosaminidase (NAG) was observed during the first 5 days after CY treatment in normal rats, but it increased in MTLn3-bearing rats. No elevation in blood urea nitrogen (BUN) or serum creatinine (Cr) values was observed for either group. Both urine volume and urinary excretion of NAG after CY treatment were lower in rats bearing the MTC clone (lower production of MMP-9) than for those bearing the MTLn3 clone. In the case of treatment with cisplatin (CDDP, 4-6 mg kg-'), urine volume, urinary NAG excretion and BUN and serum Cr values all increased in normal rats and were all found to be higher in MTLn3-bearing rats than in normal rats. The diuretic response to these drugs in tumour-bearing (TB) rats may be associated with MMP-9 produced by the tumour cells. This report suggests that the nephrotoxicity due to anti-cancer drugs may change when the drugs are used for the treatment of patients bearing a MMP-9-producing tumour.Keywords: cyclophosphamide; matrix metalloproteinase-9; nephrotoxicity; cisplatin

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“…3A and Table 2); some rats showed lower toxicity when compared with that of the previous cycle. Mizushima et al 14) have reported that when CDDP (4 mg/kg) was injected repeatedly at intervals of 3 weeks, a decrease in nephrotoxicity was observed after the 2nd injection; however, after the 3rd injection, nephrotoxicity increased. Miyaji et al 13) also reported that a rechallenge with the same dose of CDDP 14 d after the first dose of CDDP induced significantly less injury, and that the overexpression of p21 and proliferating cell nuclear antigen in rechallenge injury may contribute to the acquired resistance in CDDP-induced nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…20,21) It has been reported that the Cr concentration greatly increased 2 or 3 d after CDDP administration, reached a peak at approximately 5 d, and subsided within 10 d 13,14) ; nevertheless, Cr concentration did not return to the value before administration. 22,23) Based on this information, AKI and sCKI, as an original index in this study, were defined as the maximum Cr concentration (Cr max ) within the first 8 d (day 0-7) and the arithmetic mean Cr concentration on day 11-19 (Cr base ) of each cycle, respectively (AKI and sCKI in this study do not indicate a pathological condition).…”

Section: Animals and Materialsmentioning

confidence: 98%

“…It has been reported that the magnitude of CDDP-induced AKI is altered by the cycle; after the washout period, CDDP-induced AKI in the 2nd cycle showed less toxicity than that in the 1st cycle, 13) whereas the toxicity in the 3rd and 4th cycles was higher in an accumulative manner. 14) In addition, although CDDP-induced AKI is generally considered to be reversible, long-term CDDP treatment may induce a cumulative nephrotoxicity [sub-chronic kidney injury (sCKI)]. The creatinine (Cr) clearance in cancer patients treated with multiple CDDP cycles decreased by cycle, even with washout periods.…”

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confidence: 99%

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Alterations in Cisplatin Pharmacokinetics and Its Acute/Sub-chronic Kidney Injury over Multiple Cycles of Cisplatin Treatment in Rats

Okada

Fukushima

Fujita

et al. 2017

Biological & Pharmaceutical Bulletin

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Cisplatin (CDDP)-induced acute kidney injury (AKI) is a major clinical concern. CDDP treatment is generally conducted with multiple cycles; the magnitude of the CDDP-induced AKI may be altered by these cycles. Moreover, sub-chronic kidney injury (sCKI) induced by repeated CDDP treatment is often associated with renal interstitial fibrosis, potentially leading to chronic kidney disease. Therefore, it is suggested that the management of not only AKI but also sCKI induced by CDDP in multiple cycles plays an important role in the outcome of CDDP-based chemotherapy. This study investigated the alteration in pharmacokinetics and toxicodynamics of CDDP that was repeatedly administered for three cycles in rats; a cycle consisted of CDDP (5.0 mg/kg, bolus injection) followed by a 21-d washout period. AKI and sCKI were evaluated by plasma creatinine concentration. In repeated multiple administration of CDDP, renal clearance was decreased and the amounts of accumulated Pt in kidneys increased by the cycle. AKI and sCKI were similarly exacerbated by the cycle, whereas the degree of AKI showed a large inter-and intra-individual variation in each cycle. However, the degree of sCKI constantly increased (creatinine increasing ratio in any cycle is about 150%), suggesting that the degree of sCKI in any given cycle was predictable by monitoring the initial creatinine baseline. In this study, therefore, it is suggested that the evaluation of sCKI by monitoring creatinine concentration at base is important for the estimation of CDDP-induced nephrotoxicity. These results may provide useful information for more effective and safe CDDP-based chemotherapy with evidence-based dose adjustment.Key words cisplatin; repeated administration; pharmacokinetics; creatinine; kidney injury Cisplatin [cis-diamminedichloroplatinum (II), CDDP] is widely used as a key antitumor agent. However, despite its clinical usefulness, CDDP-induced nephrotoxicity is one of the dose-limiting side effects and a major clinical concern; recent retrospective studies have reported that approximately one-third of patients treated with CDDP-based chemotherapy experience acute kidney injury (AKI), even with plausible renoprotective strategies such as co-administration with hydration.1,2) Therefore, the prediction and prevention of CDDPinduced AKI still remain a challenge.The pharmacokinetics (PK) of CDDP and the pathophysiology of CDDP-induced AKI have been intensively investigated. A unique feature of CDDP PK is the non-specific and irreversible binding of CDDP to proteins; after administration, CDDP rapidly and irreversibly binds to plasma proteins to form inactive CDDP complexes.3,4) Therefore, irreversible binding of CDDP to plasma proteins should be considered as metabolic inactivation. Unbound CDDP is excreted mainly by glomerular filtration and partially by active transport mediated via organic cation transporter (OCT)-2 and multi-drug and toxin extrusion transporter 2.5,6) During distribution and excretion processes, CDDP accumulates in proximal tubular epithel...

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Studies on nephrotoxicity following a single and repeated administration of cis-diamminedichloroplatinum (CDDP) in rats.

Cited by 11 publications

References 9 publications

Cisplatin Nephrotoxicity in Cadmium-Pretreated Rats

Cisplatin Nephrotoxicity in Cadmium-Pretreated Rats

Diuretic response to cyclophosphamide in rats bearing a matrix metalloproteinase-9-producing tumour

Alterations in Cisplatin Pharmacokinetics and Its Acute/Sub-chronic Kidney Injury over Multiple Cycles of Cisplatin Treatment in Rats

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