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

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney hist opathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP were studied in rats, dFdC was administered intraperitoneally (i.p.) at single doses of 90 mg kg(-1) while CDDP was administered i.p. at single doses of 6 mg kg(-1). Both drugs were injected either alone or sequentially in combin ation. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other cas e, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration , the nephrotoxicity was manifested biochemically by elevation of serum cre atinine, blood urea nitrogen and an increase in the kidney weight as a perc entage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was mon itored by measuring the malondialdehyde (MDA) production level and kidney g lutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not signi ficantly change the indices of CDDP-induced nephrotoxicity or the kidney pl atinum concentration levels in comparison with those animals treated with C DDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CD DP administration significantly aggravated CDDP-induced nephrotoxicity whic h 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 wei ght. In addition, kidney tissue showed severe GSH depletion and increases i n 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 d FdC 4 h prior to CDDP. Histopathological examination demonstrated tubular a trophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treat ed group. However, pretreatment of rats with dFdC 4 h and 24 h Frier to CDD P revealed extensive interstitial nephritis, renal tubular atrophy and tubu lar necrosis with 'sloughing off' of the lining cells, especially with thos e rats treated with dFdC 24 h prior to CDDP. These results might suggest th at administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity. (C) 2001 Academic Press.