新铂类药物双环铂与顺铂、卡铂体内毒性的比较研究

目的:比较新铂类药物双环铂与顺铂、卡铂的体内毒性.方法:大鼠重复静脉注射双环铂、顺铂与卡铂,分别于给药结束以及恢复期末收集标本,进行血液学、血尿生化指标及病理切片的检测.结果:与溶剂对照组比较,重复静脉注射后,双环铂的高剂量组(13.89 mg·kg-1)全血网织红细胞以及红细胞明显降低(P＜0.01),骨髓切片示有核细胞显著减少;恢复期末网织红细胞和骨髓切片基本恢复至正常,而红细胞仍维持较低水平(P＜0.05).而双环铂各组尿酶、血尿素氮和肌苷以及肾脏病理切片在给药结束和恢复期均未见明显改变.结论:双环铂对SD大鼠的肾毒性明显低于顺铂,其骨髓抑制作用与卡铂相近,暗示肾毒性可能不会成为限制双环铂临床应用的主要毒副反应,临床应用需密切观察其对造血组织的损伤.     

微生态制剂治疗388例急性腹泻患儿的临床研究

目的比较多西他赛在不同时间点给药后的血药浓度、疗效以及毒性反应的变化,根据其节律变化选择临床最佳给药时间,获得最佳疗效。方法经病理和细胞学证实的60例III、IV期非小细胞肺癌(NSCLC)患者随机分为3组。多西他赛:A组(n=20)在8∶00 am给药,B组(n=20)在2∶00 pm给药,C组(n=20)在8∶00 pm给药;顺铂在多西他赛给药后第2天给予。多西他赛40 mg.m-2,ivgtt,d1,8;顺铂75 mg.m-2,ivgtt,d1,第21天重复。测定给药后1,10,24 h的血药浓度,并评价经化疗2个周期后的疗效和不良反应。结果3组的疗效和血药浓度在统计学上没有显著性差异,但2:00 pm,8:00 pm给药组的不良反应发生率较高。结论多西他赛治疗NSCLC在8∶00 am给药较为安全有效,可增加病例数做进一步的深入研究。     

多西他赛联合奈达铂不同给药途径治疗卵巢癌疗效观察

目的:研究多西他赛联合奈达铂不同给药途径治疗卵巢癌的疗效与不良反应。方法:82例卵巢癌患者分为静脉化疗组与腹腔化疗组各41例,前者予以多西他赛60～75 mg·m^-2静滴,24 h后予以奈达铂80 mg·m^-2静滴。后者予以多西他赛60～75 mg·m^-2静滴,24 h后予以奈达铂80 mg·m^-2腹腔内灌注。每4周为一疗程,完成2个疗程后观察疗效及不良反应。结果:静脉治疗组总有效率39.02%,腹腔内治疗组总有效率70.73%。两组比较,差异有统计学意义（P<0.05）。不良反应主要为骨髓抑制、肝功能损害、脱发、胃肠道反应、肌肉关节痛、神经毒性等。结论:多西他赛联合奈达铂腹腔内给药近期疗效优于单纯静脉给药,但肝功能损害不良反应发生率较高。     

顺铂药效和毒性作用的依时特征

目的:探索顺铂药效和毒性依时特征.方法:通过监测S180实体瘤小鼠的瘤重、外周血尿素氮和LD50评价昼夜不同时间顺铂给药的反应.结果:顺铂凌晨2:00给药作用强、毒性大,晚上18:00给药毒性小,作用弱.结论:顺铂的药效和毒性反应同步运行,对于小鼠晚上给药不良反应小,提示顺铂临床用药应避开毒性反应最大的时间.     

奈达铂联合氟尿嘧啶在晚期食管癌治疗中的临床应用价值分析

目的:分析奈达铂联合氟尿嘧啶在晚期食管癌治疗中的临床应用效果.方法:抽取75例晚期食管癌患者,按照治疗方式不同分为两组,观察组37例接受奈达铂联合氟尿嘧啶治疗,对照组38例接受顺铂联合氟尿嘧啶治疗.结果:观察组近期疗效CRP 94.6％,有效率59.5％高于对照组近期疗效CRP 81.6％,有效率28.9％,胃肠道反应较对照组轻,但骨髓抑制反应较对照组高,两组对比,P<0.05;两组远期疗效对比,P>0.05.结论:奈达铂联合氟尿嘧啶治疗晚期食管癌取得一定效果,临床不良反应少,但存在一定骨髓毒性,需进一步研究.     

吉西他滨治疗非小细胞肺癌的时辰药理学研究

目的:研究吉西他滨的时辰药理学,选择最佳给药时间,以获得最大疗效,减少毒性反应。方法:60例Ⅲ～Ⅳ期非小细胞肺癌(NSCLC)患者随机分为3组。A组(n=20)在8∶00给药,B组(n=20)在14∶00给药,C组(n=20)在20∶00给药。吉西他滨1g·m-2,ivgtt,第1、8天;顺铂75mg·m-2,ivgtt,第1天,第21天重复。测定给药后0.5、1.5、3h的血药浓度,并评价经化疗2周期后的疗效和毒副反应。结果:A、B、C组有效率分别为44.4%、35.3%、38.9%(P>0.05)。给药后3个时间点的血药浓度,3组间差异无统计学意义(P>0.05),但14∶00给药组的毒副反应发生率较高。结论:吉西他滨治疗NSCLC在8∶00给药较为安全、有效。     

奈达铂与顺铂在局部晚期宫颈癌联合化疗中的疗效比较

目的:研究奈达铂和顺铂在局部晚期宫颈癌新辅助化疗中的疗效和安全性。方法:58例巨块型局部晚期宫颈癌患者行新辅助化疗,奈达铂化疗组32例与顺铂化疗组26例均行2～3疗程静脉化疗,观察两组疗效及不良反应。结果:奈达铂组和顺铂组有效率分别为65.63%和61.54%,差异无统计学意义(P>0.05)。奈达铂组胃肠道毒性、肾毒性明显低于顺铂组(P<0.05),两组肺毒性、神经毒性、过敏反应及血液毒性(包括白细胞减少、贫血、血小板减少)无明显差异(P>0.05)。结论:奈达铂可应用于局部晚期宫颈癌新辅助治疗,值得进一步研究其临床价值。     

多西他赛治疗非小细胞肺癌的时辰药理学研究

目的 比较多西他赛在不同时间点给药后的血药浓度、疗效以及毒性反应的变化,根据其节律变化选择临床最佳给药时间,获得最佳疗效。方法 经病理和细胞学证实的60例III、IV期非小细胞肺癌(NSCLC)患者随机分为3组。多西他赛：A组(n=20)在8∶00 am给药,B组(n=20)在2∶00 pm给药,C组(n=20)在8∶00 pm给药;顺铂在多西他赛给药后第2天给予。多西他赛40 mg·m^-2,ivgtt,d1,8;顺铂75 mg·m^-2,ivgtt,d1,第21天重复。测定给药后1,10,24 h的血药浓度,并评价经化疗2个周期后的疗效和不良反应。结果 3组的疗效和血药浓度在统计学上没有显著性差异,但2:00 pm,8:00 pm给药组的不良反应发生率较高。结论 多西他赛治疗NSCLC在8∶00 am给药较为安全有效,可增加病例数做进一步的深入研究。     

顺铂用于非小细胞肺癌化疗的疗效、毒性与时间关联性研究

目的:研究顺铂用于非小细胞肺癌化疗的疗效、毒性与时间的关联性。方法:16名非小细胞肺癌化疗患者使用顺铂联合长春瑞滨方案治疗,静脉滴注给药,采用2种用药方案,分别为顺铂20mg·m-2,d1～5+长春瑞滨25mg·m-2,d1、8和顺铂60mg·m-2,d1、2+长春瑞滨25mg·m-2,d1、8。动态采集患者0～96h血液样本,采用高效液相色谱法测定给药后顺铂血药浓度,按世界卫生组织制定的疗效和毒副反应分级标准评价疗效和药品不良反应,将其按疗效和毒性反应进行分组(疗效:完全缓解+部分缓解(CR+PR)组和稳定+无效(SD+PD)组;消化道反应:0～Ⅱ度组和Ⅲ～Ⅳ度组;骨髓抑制:白细胞(WBC)减少组和WBC未减少组),分别比较2组之间不同时间点血药浓度的差异,观察其P值随时间的变化。结果:疗效、消化道反应及骨髓抑制比较,2组间P值随时间的变化均呈两端小、中间大的变化。结论:顺铂用于非小细胞肺癌化疗后0～96h,靠近0及96h两端时间点的血药浓度更能反映其疗效及毒性的变化,在所取时间点中,0.25h为最佳取血点。     

以奈达铂为主联合方案治疗非小细胞肺癌的临床观察

目的:观察3种含奈达铂联合化疗方案治疗中晚期非小细胞肺癌(NSCLC)的短期疗效及毒副反应.方法:应用含奈达铂联合化疗方案治疗20例非小细胞肺癌.化疗2周期后按WHO标准进行评价.结果: 入组20例均可以进行疗效评价, 其中完全缓解2例,部分缓解7例,稳定12例,进展1例.总有效率45.0%.毒副作用以骨髓抑制为主,但Ⅰ～Ⅱ度占多数,其中白细胞下降发生率85.0%,Ⅲ～Ⅳ度为35.0%;血小板下降为40.0%,Ⅲ～Ⅳ度为25.0%,经相应处理均可恢复,并不影响下一周期的化疗.未出现严重的肝肾功能损害的现象.胃肠道反应均为Ⅰ～Ⅱ度.结论:以奈达铂为主的3组联合化疗方案经临床初步观察有一定疗效且毒性患者可耐受,但应进一步观察研究奈达铂联合方案对NSCLC的生存率的影响.     

Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin and nedaplatin in rats

The platinum antitumour drugs cisplatin, carboplatin and nedaplatin differ in their toxicity. The relationships between the pharmacokinetics of these drugs and developed parameters for predicting their nephrotoxicity and myelosuppression were investigated. The drugs were administered to male Wistar rats by intravenous bolus or infusion, and linearity of pharmacokinetics, total clearance and the apparent ratio of tissue concentrations of unchanged drug to plasma concentration (Kp app) at steady state were determined. Apparent hydrolysis rates of each drug were determined in-vitro. Nephrotoxicity and myelosuppression were estimated by blood urea nitrogen (BUN) and platelet count, respectively. Tissue exposure to platinum was estimated as the product of the area under the plasma concentration-time curve for unchanged drug (AUC p), Kp app and the apparent hydrolysis rate constant (k hydrolysis), and toxicity factor was defined as the product of Kp app x k hydrolysis as an intrinsic drug parameter. The relationship between AUC p x toxicity factor and BUN fitted well to an Emax model. In bone marrow, this function was also correlated with platelet count. In summary, the product of AUC p x toxicity factor is a factor determining the pharmacokinetics of platinum drug-induced nephrotoxicity and myelosuppression in rats, and this toxicity factor may be a useful parameter for predicting the degree of toxicity of platinum antitumour compounds.     

Time course of the change and amelioration of nedaplatin-induced nephrotoxicity in rats

Nedaplatin (NDP) is a second-generation antineoplastic platinum complex, with reduced nephrotoxicity. Two experiments were conducted to characterize the time course of changes of its nephrotoxicity and to further evaluate whether hydration is useful for amelioration of nephrotoxicity. In the first experiment, 8-week-old male rats treated with 6 or 9 mg kg(-1) NDP at a single intravenous dose were killed 2, 4, 7 and 14 days after dosing. In the second experiment, nonhydrated (Nhyd) or hydrated (Hyd) rats, treated with a single intravenous dose of 20 mg kg(-1) NDP, were killed 7 days after dosing. Besides renal function and histopathological examinations, the urinary excretion of platinum was measured. Histopathologically, NDP-induced nephrotoxicity was initially characterized by single cell and/or focal necrosis in the epithelium of distal tubules and collecting ducts as well as proximal tubules. In the later stage, subsequent cystic dilatation and regeneration occurred in these affected tubules, but incomplete tissue repair was still observed in the kidney 14 days after dosing. However, NDP-induced nephrotoxicity was dramatically reduced by hydration, while it had no clear effects on myelotoxicity. Measurement of urinary platinum excretion revealed that the total amount of platinum excretion was significantly higher in Hyd-NDP rats than that in Nhyd-NDP rats. In terms of urinary concentration, Hyd-NDP rats showed a lower concentration compared with that in Nhyd-NDP rats. The current results suggest that NDP has the potential risk to cause nephrotoxicity at a human therapeutic dose without hydration and that pre- and post-hydration at dosing can ameliorate this nephrotoxicity.     

Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of Cyclosporine A after multiple dosing

The aim of this study was to test the ability of poly(ethylene oxide)-b-poly (epsilon-caprolactone) (PEO-b-PCL) micelles to reduce the renal uptake and nephrotoxicity of Cyclosporine A (CyA) after multiple dose administration. Sprague-Dawley rats received CyA i.v. at a dose of 20 mg/kg/day delivered as the commercial formulation (Sandimmune) or polymeric micellar formulation (PM-CyA). Cremophor EL (the solubilizing agent in Sandimmune), unloaded PEO-b-PCL micelles, or normal saline were also administered i.v. to control rats. After 7 days, kidney function was assessed through measurement of creatinine (CLcr) and urea clearances, as well as electrolyte concentrations in plasma. Blood and kidney were collected and assayed for CyA. Sandimmune administration led to decreased CLcr, and increased urea and potassium levels in plasma. In contrast, functional nephrotoxicity with the PM-CyA was not apparent, as the CLcr did not change significantly. The rate of increase in body weight in control rats was 3.1-3.4% per day. Weight gains (1.8% per day) were also noted in the rats given PM-CyA, although the body weight of animals receiving Sandimmune remained constant. Compared to Sandimmune, polymeric micelles reduced kidney uptake of CyA by 2.6-fold, and increased CyA levels in blood by 2.1-fold. The results show a potential for PEO-b-PCL micelles in restricting the nephrotoxicity of CyA.     

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.     

Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients

AIMS: The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis-diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter- and intra-individual variability were evaluated. METHODS: In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter- and intra-individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data-splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated. RESULTS: A two-compartment pharmacokinetic model with zero-order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) [population mean [95% confidence interval (CI)] CL (l h(-1)) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) x CLcr (CLcr: ml min(-1))] and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) x BW]. Inter-individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra-individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were - 0.0164 micro g ml(-1) (- 0.4379, 0.4051) and 0.2155 micro g ml(-1) (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well. CONCLUSIONS: A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.     

Chronopharmacological study of physical dependence on morphine in rats

Relationship between withdrawal time or naloxone injection time and withdrawal signs were examined in morphine-treated rats. Sixty-five rats were treated chronically with morphine-admixed food (1 mg/g food) for 7 days and were divided into 13 groups. The rats of 4 groups were abruptly withdrawn from morphine, and the rats of another 4 groups were given naloxone (3 mg/kg, s.c.) at 20:00 on the 8 th day and 2:00, 8:00 and 14:00 on the 9 th day after the morphine administration, respectively. Withdrawal signs were observed at intervals of 2 hr. After each naloxone injection, abnormal behaviors were observed for 60 min, and body weight was measured for 3 hr at intervals of 15 or 30 min. In the withdrawal test, weight loss at 24 hr after withdrawal in each group was approximately 10%, and there was no difference between each group. However, the body weight of non-treated rats and morphine-treated rats increased during the night period (20:00-8:00) and decreased during the daytime (8:00-20:00). Therefore, body weight reached the minimum at 20:00, and then this time is appropriated for withdrawal. In the naloxone test, withdrawal signs in the night period were more potent than that in the daytime. The withdrawal signs induced by naloxone at 8:00 showed the maximum magnitude. Plasma morphine levels in rats treated with morphine-admixed food were high in the night period and low in the daytime. These results suggest that the magnitude of naloxone-precipitated withdrawal signs depends on the amount of morphine in the plasma.     

奈达铂治疗中晚期食管癌41例临床分析

目的 观察奈达铂联合亚叶酸钙和氟尿嘧啶治疗中晚期食管癌的疗效及毒副反应.方法 41例中晚期食管癌患者,应用奈达铂联合亚叶酸钙和氟尿嘧啶联合化疗方案,评价近期疗效及毒副反应.结果 41例患者总有效率为41.5%.主要毒副作用为血液学毒性,消化道副反应及肝肾毒性等轻微.结论 奈达铂联合亚叶酸钙和氟尿嘧啶联合化疗治疗中晚期食管癌疗效良好,不良反应可以耐受,值得临床推广使用.     

Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.     

Nephrotoxicity of a novel antineoplastic platinum complex, nedaplatin: a comparative study with cisplatin in rats

The present study was designed to characterize the nephrotoxicity induced by the antineoplastic platinum complex nedaplatin (NDP) in rats of different ages in comparison with cisplatin (CDDP). A single dose of 15 mg/kg NDP or 7.5 mg/kg CDDP was administered intravenously to 8-, 11-, or 15-week-old male and female SD rats, which were then sacrificed after ten days. Body weight decreases were observed for both drugs, in direct relation to age. CDDP treatment markedly increased urinary excretion of NAG, -GTP, LDH and protein, with peaks on day 4 and complete or partial recovery on day 7; NDP increased NAG, LDH and protein excretion, but to a lesser extent, and these elevations were generally more marked for females. CDDP increased plasma creatinine and BUN in males and females of all age groups at necropsy. No apparent changes were seen following NDP treatment except in the 15-week-old rats. These results also show that NDP is less nephrotoxic than CDDP. CDDP-treated rats showed remarkable proximal tubular lesions in the renal cortex and corticomedullary region, and the papillary lesions were minor. On the other hand, the NDP-induced nephrotoxicity was morphologically characterized by hyaline droplet changes (electron microscopically, hyperplasia of lysosomes), necrosis or hyperplasia of the collecting duct epithelium in the renal papilla and the epithelium covering the papilla. Cortical lesions, indicated by slight tubular dilatation, were found only in the animals with papillary lesions. In summary, NDP is a promising second-generation platinum complex with reduced nephrotoxicity.     

Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6mg kg(-1)) for 5 days at four time points (04:00, 10:00, 16:00 and 22:00h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04:00 and 16:00h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04:00 and 16:00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04:00 and the 16:00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16:00 h group than in the 04:00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.