Comparative study of cisplatin and carboplatin on pharmacokinetics, nephrotoxicity and effect on renal nuclear DNA synthesis in rats.

To clarify the difference in nephrotoxicity between cisplatin and carboplatin, the pharmacokinetics of platinum, renal function and nuclear DNA synthesis in renal cortical and outer medullary cells were studied in rats which had received cisplatin or carboplatin. Male Sprague-Dawley rats were given either cisplatin or carboplatin intravenously at an equi-toxic dose (LD10 or LD50) and were killed at various times within 7 days after the injection. Cisplatin bound to plasma proteins more avidly than carboplatin. Much more platinum was detectable in the renal nuclei after cisplatin injection than after carboplatin injection. BUN and serum creatinine levels in the rats treated with 8.5 mg/kg of cisplatin were significantly higher than in those treated with 100 mg/kg of carboplatin. Cisplatin markedly suppressed the renal nuclear DNA synthesis both in vivo and in vitro, when compared with carboplatin. It is concluded that the differences in nephrotoxicity between cisplatin and carboplatin are related to their different inhibitory effects on nuclear DNA synthesis in the renal cells.     

Ultrastructural alterations and DNA synthesis of renal cell nuclei following cisplatin or carboplatin injection in rats.

To clarify the difference in nephrotoxicity between cisplatin and carboplatin, ultrastructural alterations and DNA synthesis of renal cell nuclei were studied in Sprague-Dawley rats which had received intravenously either cisplatin or carboplatin at an equitoxic dose. Twelve hours after cisplatin injection, nucleolar segregation accompanied by aggregated nuclear heterochromatin was observed in the third segment of the proximal tubules. Seventy-two hours after cisplatin injection, nuclear damage was more widespread while regenerative cells were also observed. Nuclear damage was not observed in the carboplatin-treated rats. Nuclear DNA synthesis of renal cells was suppressed at 8, 12 and 24 h and was accelerated at 72 h after cisplatin injection. Carboplatin did not suppress nuclear DNA synthesis at any time. The results indicate that cisplatin, but not carboplatin, can affect the renal cell nuclei. Cisplatin-induced nephrotoxicity is related to its effects on renal cell nuclei.     

大鼠静脉注射3种铂制剂后铂的肾排泄与肾分布比较研究

目的:探讨铂类抗癌药的肾毒性机制。方法:12只大鼠均分为3组,分别按铂元素10mg·kg-1剂量静脉注射顺铂、卡铂和双环铂,采用原子吸收法测定并计算4h尿药累积排泄率及肾组织中浓度。结果:4h累积排泄率顺铂、卡铂、双环铂分别平均为(33.7±5.7)%、(89.1±8.5)%、(70.1±9.8)%,肾组织中铂的浓度分别为(70.6±31.6)、(217.7±97.6)、(278.8±112.0)μg.g-1。结论:与顺铂相比,双环铂与卡铂肾排泄较快,肾组织中的铂浓度相对较高;肾组织中铂浓度高低与肾毒性大小之间可能无直接关系。     

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug–drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.     

Experimental studies on the pharmacokinetics and nephrotoxicity of carboplatin (cis-diammine-1, 1-cyclobutane dicarboxylate platinum II) in rats

To study the nephrotoxicity of carboplatin (cis-diammine-1, 1-cyclobutane dicarboxylate platinum II, CBDCA), an analogue of cisplatin, we examined its pharmacokinetics and functional and histopathological changes of the kidney in rats that received i.v. injection of carboplatin. Platinum concentrations in the whole plasma rapidly decreased during the first 2 hours and was undetectable at 72 hours following the carboplatin administration. Approximately 90% of the platinum in the whole plasma was ultrafilterable during the first 30 minutes. The renal tissue concentrations of platinum rapidly decayed during the first 4 hours and then slowly declined up to 120 hours following the carboplatin administration. Platinum concentrations in the renal cortex showed higher levels than those in the renal medulla throughout the experimental period. BUN levels were within the normal range except on day 7. Serum creatinine levels remained stable and normal during the 7 days. Histopathological alterations of the renal tubules were not observed during the experimental period. These results suggest that carboplatin has less nephrotoxicity than cisplatin, because of its rapid excretion through glomerulus and less accumulation in the tubular cells.     

The renal fractional clearance of platinum antitumour compounds in relation to nephrotoxicity

The fractional renal clearance of platinum relative to inulin was measured in the conscious rat during the period 60-70 min after injection of the nephrotoxic drug, cisplatin, or its non-nephrotoxic analogues (trans-dichlorodiammine platinum II, carboplatin or iproplatin). The fractional clearance of platinum was between 3 and 4 for cisplatin and its analogues. Platinum from cisplatin and its trans isomer is essentially irreversibly bound whilst that from carboplatin and iproplatin is largely reversibly bound to blood proteins. Probenecid and triethanolamine both caused an increase whereas furosemide caused a decrease in the fractional clearance of total platinum from cisplatin. Choline chloride had no nett effect on the fractional clearance of total platinum. Both furosemide and triethanolamine made no significant difference to the severity of cisplatin induced nephrotoxicity. However, probenecid enhanced cisplatin induced nephrotoxicity and choline chloride was capable of blocking cisplatin induced nephrotoxicity. We conclude that the renal tubular transport of platinum is not per se responsible for the nephrotoxicity of platinum compounds. However, in the case of cisplatin, or one of its metabolites, renal tubular transport may be a prerequisite for nephrotoxicity.     

Pharmacokinetics and toxicodynamics of cisplatin and its metabolites in rats: relationship between renal handling and nephrotoxicity of cisplatin

The renal handling of cisplatin and its metabolites and the relationship between the pharmacokinetics of these platinum species in the kidney and nephrotoxicity in rats were studied by carrying out pharmacokinetic-pharmacodynamic analysis. Rats received cisplatin intravenously as a bolus (2-10 mgkg(-1)) or by constant infusion (55 and 140 microg min(-1) kg(-1)). After intravenous administration of each platinum species, the platinum concentrations of unchanged cisplatin and its mobile and fixed metabolites were determined separately. Nephrotoxicity was estimated by measuring the blood urea nitrogen (BUN) levels and the sigmoid Emax model was used to determine the relationship between pharmacokinetic parameters and BUN levels 5 days after cisplatin administration. Cisplatin and its mobile metabolites in plasma distributed more rapidly and extensively into the kidney (mean apparent kidney-to-plasma concentration ratios were 2.69 and 7.12 mL (g tissue)(-1), respectively) than into the liver (less than 1 mL (g tissue)(-1)). Concomitant administration of mobile metabolites did not significantly alter the disposition of cisplatin. Nephrotoxicity, estimated by measuring BUN levels, appeared to be related to the plasma concentration of intact cisplatin, not total platinum, because mobile metabolites formed from cisplatin showed little nephrotoxicity. The sigmoid Emax model showed the maximum BUN level reached after cisplatin administration was related to the area under the renal cisplatin concentration-time curve (AUCk).     

Comparative Nephrotoxicity of a Novel Platinum Compound, Cisplatin, and Carboplatin in Male Wistar Rats

The nephrotoxicity of three platinum-containing antitumor agentswas compared at doses that approximate the LDIO (cisplatin)or the LD5O (CI-973, carboplatin) doses. Male Wistar rats wereadministered single iv doses of 45 mg/kg CI-973, 6.5 mg/kg cisplatin,or 65 mg/kg carboplatin and observed for 4 days. Cisplatin treatmentincreased blood urea nitrogen (4X), creatinine (3x), glucose,and fractional electrolyte excretions, and decreased creatinineclearance by Day 4. These parameters were not significantlyaltered in CI-973- and carhoplatin-treated animals. Cisplatinincreased urinary excretion of LDH (six fold), GGT (twofold),and NAG (twofold); CI-973 and carbo platin increased GGT excretion(approximately twofold). Cis platin induced the following functionalchanges as a conse quence of direct nephrotoxicity: decreasesin GFR (84%), ERPF (97%), ERBF (96%), and ERTS (95%), and increasesin FF (fivefold). Functional changes, attributed to prerenaleffects of CI-973, included a decrease in ERPF (35%) and anincrease in FF (48%). No changes were seen following carboplatintreat ment. All cisplatin-treated rats had proximal tubularnecrosis in the outer stripe of the outer medulla, extendingmultifocally into inner cortical medullary rays. No renal lesionswere de tected by light or electron microscopy in the controlor Cl-973- or carboplatin-treated rats. Cisplatin produced markednephro toxicity as determined by biochemical, functional, andhisto pathologic endpoints. CI-973 and carboplatin were significantlyless nephrotoxic than cisplatin.     

Renal accumulation and urinary excretion of cisplatin in diabetic rats.

Previous work has demonstrated that cisplatin nephrotoxicity was attenuated in streptozotocin (STZ)-induced diabetic rats. The following studies investigated the hypothesis that renal cisplatin accumulation was reduced in diabetic rats. Male Fischer 344 (F344) rats were injected with 32 mg/kg STZ (i.p.) or citrate buffer. Renal platinum (Pt) accumulation was quantitated 0-96 h after the administration of 5 mg/kg cisplatin (i.p.) to normoglycemic and diabetic rats (greater than or equal to 4/group). Total renal Pt accumulation was decreased (P less than 0.05) in the diabetic rats, when compared to the normoglycemic group, 6-48 h after cisplatin injection. Further studies were also conducted to examine if urinary cisplatin excretion was enhanced in diabetic relative to normoglycemic groups. Urinary Pt excretion was quantitated 0-96 h following cisplatin (5 mg/kg, i.p.) administration. Pt excretion was increased in the diabetic group relative to the normoglycemics when comparisons were made on the basis of Pt excreted per hour or cumulative Pt excretion. Differences were also detected in urinary Pt concentration. The diabetic group had a lower urinary concentration of the metal 12-96 h after cisplatin injection. These findings suggest that the reduction in nephrotoxicity in diabetic rats may be at least partially due to decreased renal accumulation as well as altered renal excretion.     

Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity

The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-beta-D-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H(+)/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H(+)-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families.     

Effect of cisplatin on calcium uptake by rat kidney cortical mitochondria

The effect of the nephrotoxic antineoplastic drug, cisplatin, on mitochondrial calcium uptake was examined in rat kidney cortical mitochondria. We treated rats with cisplatin (5 mg/kg, i.p.), and prepared and incubated the mitochondria. Uptake of calcium decreased after 24 h. The mitochondria contained platinum even 3 days after injection. Cisplatin (0.5 mM) added to incubation medium inhibited calcium uptake. Platinum accumulated in the mitochondria during incubation. Mitochondria accumulated less of another divalent cation, magnesium, in rats given cisplatin and in incubation medium with cisplatin added. The results suggest that cisplatin taken up into kidney cortical mitochondria inhibited divalent cation uptake there, which may contribute to cisplatin nephrotoxicity.     

Attenuation of Cisplatin Nephrotoxicity by Streptozotocin-Induced Diabetes

Attenuation of Cisplatin Nephrotoxicity by Streptozotocin-InducedDiabetes. SCOTT, L. A., MADAN, E., AND VALENTOVIC, M. A. (1989).Fundam. Appl. Toxicol 12, 530–539. The thera peutic useof cisplatin is associated with acute renal failure. The purposeof this study was to determine (a) if streptozotocin (STZ) wastoxic to renal proximal tubules and (b) the nephrotox icityof cisplatin in STZ-diabetic rats. Male Sprague-Dawley ratswere injected with STZ (55 mg/kg, ip) to induce a diabetic state.BUN and renal cortical slice uptake of p-aminohippurate (PAN)and tetraethylammonium (TEA) were not altered, relative to normoglycemicrats, 3, 16, and 28 days following STZ treatment. These resultsindicate that STZ is not toxic to renal proximal tubules. Cisplatinnephrotoxicity studies were then conducted in STZ-diabetic andnormo glycemic rats. Cisplatin nephrotoxicity was also evaluatedin diabetic rats pretreated for 8 days with insulin. Diabeticand normoglycemic rats were administered 5 mg/kg cisplatin orwater (ip). Increased kidney weight, BUN levels, glucosuna,and proteinuria were measured in normoglycemic rats 4 days aftercisplatin administration. Renal cortical TEA and lactate-stimulatedPAH uptake (p<0.05) were diminished in the normoglycemicrats 4 days after cisplatin injection. No change in kidney weight,BUN levels, or renal cortical slice accumulation of PAH andTEA was observed in diabetic rats treated with cisplatin. However,cisplatin administration to diabetic rats pretreated with insulinresulted in increased mortality, proteinurla, glucosuna andelevated kidney weight. These results indicate that the diabeticstate attenuates cisplatin nephro toxicity. Additionally, theseresults indicate that diabetes attenuation ofcisplatin nephrotoxicityis dependent on the severity of the diabetic state.     

Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat

Cisplatin is an effective anticancer drug, but has its severe adverse effects, especially nephrotoxicity. The molecular mechanism of cisplatin-induced nephrotoxicity is still not clear. In the present study, we examined the role of rat (r)OCT2, an organic cation transporter predominantly expressed in the kidney, in the tubular toxicity of cisplatin. Using HEK293 cells stably expressing rOCT2 (HEK-rOCT2), we evaluated the cisplatin-induced release of lactate dehydrogenase and the uptake of cisplatin. The release of lactate dehydrogenase and the accumulation of platinum were greater in HEK-rOCT2 cells treated with cisplatin than in mock-transfected cells. Moreover, cimetidine and corticosterone, OCT2 inhibitors, inhibited the cytotoxicity and the transport of cisplatin in HEK-rOCT2 cells. Pharmacokinetics of cisplatin was investigated in male and female rats because the renal expression level of rOCT2 was higher in male than female rats. The renal uptake clearance of cisplatin was greater in male than female rats, while the hepatic uptake clearance was similar between the sexes. In addition, glomerular filtration rate and liver function were unchanged, but N-acetyl-β-d-glucosaminidase activity in the bladder urine and the urine volume were markedly increased 2 days after the administration of 2 mg/kg of cisplatin in male rats. Moreover, cisplatin did not induce the elevation of urinary N-acetyl-β-d-glucosaminidase activity in the castrated male rats whose renal rOCT2 level was lower than that of the sham-operated rats. In conclusion, the present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity.     

The Protective Effect of Glycine in Cisplatin Nephrotoxicity: Inhibition with NG-Nitro-l-arginine Methyl Ester

Abstract— The effect of glycine on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin was investigated in the rat. Cisplatin (6·0 mg kg^?1, i.v.) injection in anaesthetized rats produced, over a period of 2 h, falls of approximately 50% in renal blood flow (RBF) and the clearance of [³H]inulin (CL_IN), effects which were prevented by co-administration of glycine (1·0 g kg^?1). Infusion of the nitric oxide (NO) synthase-inhibitor N^G-nitro-l -arginine methyl ester, l -NAME (10 μg min^?1 kg^?1, i.v.), abolished glycine's ability to maintain RBF in cisplatin-injected rats whilst partially inhibiting the ability of glycine to preserve CL_IN. Treatment of cisplatin-injected rats with glycine (1·0 g kg^?1, i.v.) significantly ameliorated the nephrotoxic effects of cisplatin (6·0 mg kg^?1) as judged by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, CL_IN and the clearance of [¹⁴C]p-aminohippurate. Administration of l -NAME (1·0 mg kg^?1, i.v.) to rats which received cisplatin and glycine significantly inhibited the reno-protective effect of glycine. However, l -NAME administration to rats which were treated only with cisplatin did not result in any potentiation of cisplatin nephrotoxicity. The findings of this study suggest that glycine can block the acute falls in RBF and C_IN produced by cisplatin by a mechanism which involves the production of NO. Furthermore, the results indicate that these renal haemodynamic actions of glycine are responsible, at least in part, for the ability of this amino acid to ameliorate cisplatin nephrotoxicity.     

Comparative Toxicity and Renal Distribution of the Platinum Analogs Tetraplatin, CHIP and Cisplatin at Equimolar Doses in the Ficher 344 Rat

Comparative Toxicity and Renal Distribution of the PlatinumAnalogs Tetraplatin, CHIP, and Cisplatin at Equimolar Dosesin the Fischer 344 Rat. SMITH, J. H., SMITH, M. A., LITTERST,C. L., COPLEY, M. P., UOZUMI, J., AND BOYD, M. R. (1988). Fundam.Appl Toxicol. 10, 45-61. Tetraplatin [tetrachloro(dl-frans)1,2-diaminocyclohexane platinum(IV), NSC-363812] is a new anticancerplatinum drug analog targeted for clinical development becauseof its effectiveness against cisplatin-resistant tumor celllines and its improved formulation. The toxicity of tetraplatinwas compared at equimolar doses to that of cisplatin [cis-diamminedichlorophati-num(II)]and CHIP [cts-dichloro,trans-dihydroxybis-isopropylamine platinum(IV),NSC-256927], Adult male Fischer 344 rats received an iv bolusinjection of 6.7, 13.3, 26.7, or 53.3 µmol/kg of one ofthese drugs in saline and were killed on Day 1, 3, 5, 8, or15 postinjection for assessment of toxicity with emphasis onevaluation of nephrotoxicity. Rats to be killed on Day 15 werehoused in metabolism cages for daily urine collection. Tetraplatinwas less nephrotoxic than cisplatin at equimolar doses; CHIPwas not nephrotoxic at these doses. Renal platinum contentswere similar after all three drugs and did not appear to berelated directly to the nephrotoxicity. Nephrotoxicity was detected4–5 days after 6.7 µmol/kg cisplatin, was localizedto the corticomedullary junction, and progressed with time anddose. Tetraplatin-induced alterations of renal function werefirst observed after 13.4 µimol/kg on Day 4 as an elevationof urine volume (up to 10-fold) and a smaller elevation of urinaryglucose excretion. Tetraplatin lesions were localized in themid- and outer cortex and, even at the highest dose, were lesssevere than those observed with cisplatin. There were otherprominent toxic effects of tetraplatin, such as gastrointestinaltoxicity and myelosuppression, which indicate that factors otherthan comparative nephrotoxicity may impact the clinical potentialof this new agent.     

Amelioration of Cisplatin Nephrotoxicity with Glycine: Dose Dependency in Rats

The effects of glycine (0·1-1·0 g μg kg^?1, i.v.) on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin (6·0 mg g kg^?1, i.v.) were investigated in the rat. Cisplatin produced decreases of 50% in the clearance of [³H] inulin (C_IN) and renal blood flow (RBF), 110 min following its injection. Glycine at a dose of 0·1 g kg^?1 produced no attenuation of the cisplatin-induced decrease in C_IN or RBF. Furthermore, this dose of glycine provided no significant protection of renal function over a 7-day period following cisplatin injection. By contrast, glycine at a dose of either 0·5 or 1·0 g kg^?1 markedly attenuated cisplatin-induced falls in C_IN and RBF, with the highest dose completely preventing any falls in these indices during the course of the experiment. Treatment with these higher doses of glycine produced prominent protection from the nephrotoxic actions of cisplatin, as evidenced by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, C_IN and the clearance of [¹⁴C]P-aminohippurate. The results of experiments with an intermediate dose of 0·25 g kg^?1 glycine revealed some degree of amelioration of acute renal haemodynamic effects of cisplatin, particularly with regard to C_IN; whilst in the nephrotoxicity study, 0·25 g kg^?1 glycine produced a modest but significant reduction in cisplatin-induced acute renal dysfunction. The results have revealed a clear association between the acute renal haemodynamic effects produced by glycine in cisplatin-injected rats with the longer-term renal protective effects of glycine in cisplatin nephrotoxicity. The findings indicate that glycine's ability to prevent the falls in RBF and glomerular filtration rate produced by cisplatin plays an important role in the protective effect of glycine in cisplatin-induced nephrotoxicity.     

A study of the protective effect of chloride salts on cisplatin nephrotoxicity

In rats NaCl and NH4Cl (25 mmoles/kg, p.o.) were found to be equally effective at preventing nephrotoxicity when administered to rats 90 min before cisplatin (5 mg/kg i.p.) but (NH4)2SO4 did not protect. The severity of nephrotoxicity, taken as the maximum elevation in blood urea concentration, showed a high degree of correlation with urinary chloride concentration, but not with urinary pH or volume. Sodium chloride did not protect against nephrotoxicity when administered 3 or 24 hr after cisplatin. Sodium chloride showed protection against nephrotoxicity caused by cisplatin metabolites only at low doses of platinum. For animals pretreated with NaCl (25 mmoles/kg) or water p.o. the urinary excretion of total platinum, cisplatin and six of the seven metabolites separated by hplc was not significantly different between the two treatments during the 0-5-hr period post dosing. However, one metabolite, possibly a nephrotoxic hydrolysis product, was excreted in significantly smaller amounts in the urine of animals pretreated with NaCl (P less than 0.05). Furthermore, in all cisplatin treated animals the amount of this species excreted correlated with the severity of nephrotoxicity. Whilst this suggests that chloride ions may protect against the nephrotoxicity of cisplatin by inhibiting its rate of metabolism this metabolite accounts for only 2.5% of the platinum excreted. Furthermore, the data do not exclude the possibility that NaCl prevents cisplatin-induced nephrotoxicity by preventing renal ischaemia, which may normally follow cisplatin treatment, or that the renal uptake or transport of platinum may be inhibited by NaCl.     

Effect of methotrexate on the pharmacokinetics and renal excretion of cisplatin

Summary The kinetics of platinum in plasma and erythrocytes, and its renal excretion, have been examined in five patients with non-small cell carcinoma of the lung, after treatment with cisplatin 50 mg/m² (Platidiame) and, three weeks later, a combination of 50 mg/m² cisplatin and 40 mg/m² methotrexate. The patients were given 0.9% saline 11 l h prior to drug application.Plasma platinum elimination was biphasic with a short initial phase (t_1/2a 10–31 min) and a long-phase (t_1/2 65–91 h). With the exception of increased AUC values in all five patients 0–8 h after the injection, no significant change in the kinetics of platinum in plasma was found after coadministration of methotrexate.In four of the five patients renal platinum excretion was reduced in the first 6 h after administration of methotrexate. The renal clearance of platinum was 50% lower in those four patients 0–3 h after the injection.With the exception of one patient, no signs of nephrotoxicity were observed after combined drug administration. Other toxic effects were mild and showed no increase after the initial administration of methotrexate.     

Protective effects of capsaicin against cisplatin-induced nephrotoxicity in rats

Cisplatin-induced nephrotoxicity is related to an increase in lipid peroxidation and oxygen free radicals in a kidney. In the present study, we investigated the effect of the dietary antioxidants, capsaicin (Cap), against cisplatin-induced lipid peroxidation and nephrotoxicity in rats. Nephrotoxicity induced by treatment with a single dose of cisplatin (5 mg/kg body weight i.p.). The animals were divided into 4 groups. Cap (10 mg/kg/d) was given by gavage from the same day of cisplatin injection. Cisplatin administration resulted in significant increases in the kidney weight as a percentage of the total body weight, urine volume, serum creatinine, and blood urea nitrogen by about 132, 315, 797, and 556% in comparison with the control rats, respectively (p < 0.05). Also, the renal tissue from the cisplatin-treated rats showed significant decreases in the kidney glutathione (GSH) content and superoxide dismustase (SOD) activity and a significant increase in malondialdehyde (MDA) production in comparison to the values at 0 h (p < 0.05). Seven days after Cap plus cisplatin treatments, the renal damage induced by cisplatin recovered to a significant statistically level. In addition, Cap prevented the rise of MDA and the reduction of SOD activities. These results suggest that Cap has protective effects against cisplatin-induced nephrotoxicity and lipid peroxidation in rats.     

Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Treatment with cisplatin is associated with dose‐limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β₁‐adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor‐alpha, caspase‐3, angiotensin II and endothelin‐1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre‐treatment with N_ω‐nitro‐L‐arginine methyl ester, the non‐specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin‐induced nephrotoxicity that is most likely through its antioxidant, anti‐inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin‐1 levels.