ABSTRACT
The effects of treatment schedule on the interaction between cisplatin [CDDP] and doxorubicin [DOX] were studied in male New Zealand rabbits. Rabbits were divided into three groups., five animals each. Group I received the two drugs simultaneously while group II animals were treated sequentially with DOX one hour post CDDP administration. A third control group was injected with normal saline. Both drugs were injected as an IV. bolus of equal doses, 4 mg/kg each, and their concentrations were determined by spectrofluorometry and flameless atomic absorption spectrometry, respectively. Toxicity was assessed biochemically by estimating indices of nephrotoxicity and tissue peroxidative alterations in terms of malondialdehyde MDA production levels and non-protein sulfhydryl group contents as well as histopathological examination of kidney, heart and liver tissues. Both treatment schedules showed significant increases in serum creatinine and urea levels [p<0.01]. Also, both treatment schedules showed significant increase in MDA production levels and depletion of non-protein sulthydryl group contents in the kidney, heart and liver tissues [p<0.001]. All previous changes were aggravated with sequential administration of CDDP-DOX combination in comparison with the simultaneous one. Furthermore, histopathological examination revealed that sequential CDDP-DOX combination produced significant pathological changes in the rabbits kidney, heart and liver tissues in comparison with those animals treated simultaneously. These results were confirmed by studying the phaimacokinetics of both drugs. The plasma concentration time data for both drugs were fitted into an open two compartment model. DOX pharmacokinetics was significantly altered in the sequentially treated group [p<0.001]. The distribution and elimination half lives for the simultaneously and sequentially treated groups were 0.06 +/- 0.0095 h vs 0.104 +/- 0.0287 hand 3.48 +/- 0.5 11 h vs 18.96 +/- 3.7 h, respectively. The total body clearance in the two groups were 17.64 +/- 1.28 mI/min and 3.31 +/- 0.68 mI/min, respectively. The mean resident time [MRT] and total area under the curve [AUC] were 4.77 +/- 0.689 h and 3.8 +/- 0.26 pg/mI x h vs 26.82 +/- 5.34 h and 20.92 +/- 4.76 pg/mI x h, respectively. The volume of distribution at steady state [V] was 5.02 +/- 0.58 L vs 5.15 +/- 0.291 L, respectively. The pharmacokinetics of CDDP was not affected by changing the treatment schedule [p>0.05]. The only significant change observed was in the distribution half-life, where it appeared to be 0.09 1 +/- 0.054 h and 0.33 1 +/- 0.047 h for simultaneously and sequentially treated animals, respectively. In conclusion, sequential administration of CDDP at one hour prior DOX injection was associated with dramatic changes in the pharmacokinetics of DOX. This might contribute to aggravation of DOX-induced cardiotoxicity as well as hepatorenal toxicity of both drugs