Saad S Y, Najjar T A, Noreddin A M, Al-Rikabi A C
Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Pharmacol Res. 2001 Feb;43(2):193-8. doi: 10.1006/phrs.2000.0764.
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.
在大鼠中研究了吉西他滨（dFdC）对抗肿瘤药物顺铂（CDDP）肾毒性中脂质过氧化和肾脏组织病理学的影响。dFdC以90 mgkg(-1)的单剂量腹腔注射（i.p.），而CDDP以6 mgkg(-1)的单剂量腹腔注射。两种药物单独注射或顺序联合注射。在一种情况下，CDDP在dFdC之前4小时和24小时注射，在另一种情况下，dFdC在CDDP之前4小时和24小时注射。CDDP给药7天后，肾毒性在生化方面表现为血清肌酐、血尿素氮升高以及肾脏重量占总体重的百分比增加。此外，观察到血清白蛋白和钙水平显著降低。通过测量丙二醛（MDA）产生水平和肾脏谷胱甘肽（GSH）含量来监测肾脏中的脂质过氧化，二者分别升高和减少。与单独用CDDP治疗的动物相比，在CDDP给药后4小时和24小时给予dFdC并没有显著改变CDDP诱导的肾毒性指标或肾脏铂浓度水平。相反，在CDDP给药前4小时和24小时给予dFdC显著加重了CDDP诱导的肾毒性，表现为血清肌酐和血尿素氮水平以及肾脏重量占总体重的百分比严重增加。此外，肾脏组织显示严重的GSH耗竭以及MDA产生和铂浓度水平增加。而且，与在CDDP前4小时用dFdC治疗的动物相比，在CDDP前24小时用dFdC治疗大鼠导致CDDP诱导的肾毒性加重得更多。组织病理学检查显示CDDP治疗组有肾小管萎缩、肾小管坏死和药物诱导的核变化。然而，在CDDP前4小时和24小时用dFdC预处理大鼠显示广泛的间质性肾炎、肾小管萎缩和肾小管坏死，伴有衬里细胞“脱落”，尤其是在CDDP前24小时用dFdC治疗的大鼠中。这些结果可能表明在CDDP之前给予dFdC会增强肾脏组织中的脂质过氧化并加重CDDP诱导的肾毒性。
