Key result
The diabetic state protected against cisplatin-induced nephrotoxicity in rabbits, with nondiabetic controls exhibiting significantly higher serum creatinine and urea levels (p < 0.001).
In a rabbit model, streptozotocin-induced diabetes protected against cisplatin-induced nephrotoxicity without significantly altering the plasma pharmacokinetic profile within the first 4 hours.
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Hypothesis-generating for diabetes as renoprotective in cisplatin models; should not yet change clinical practice.
BACKGROUND: This study was designed to investigate the relationship between the attenuation of cisplatin (CDDP)-induced nephrotoxicity in experimental diabetic rabbits and the plasma pharmacokinetics of the free ultrafilterable and total plasma platinum (Pt) levels. METHODS: Two groups of age-matched male New Zealand white rabbits were used; the first group consisted of rabbits with streptozotocin-induced diabetes (single i.v. bolus dose of streptozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of nondiabetic rabbits treated with the same volume of citrate buffer. Both groups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after induction of the diabetic state in the first group. The plasma Pt levels were followed for 4 h after CDDP administration, in which the free ultrafilterable and total plasma Pt concentrations were determined by atomic absorption spectrometry. The pharmacokinetic parameters of free ultrafilterable plasma Pt were determined using a noncompartment pharmacokinetic model of analysis. RESULTS: The total plasma Pt levels declined in a biphasic manner and were adequately described by a two-compartment model. No significant change was observed in the pharmacokinetics of either the free ultrafilterable or total plasma Pt levels in the diabetic group in comparison with the control nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher than that of the diabetic rabbits (p < 0.001). Indices of nephrotoxicity were determined 7 days after CDDP administration. The results revealed that the diabetic state protected against CDDP-induced nephrotoxicity. The nondiabetic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in comparison with the diabetic group. CONCLUSIONS: These findings might suggest that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug follow-up period. It could be anticipated that the rapid decline in the total plasma Pt level after CDDP administration to diabetic rabbits, as well as the reduction in the terminal elimination half-life of the total plasma Pt level might be responsible for the reduction in CDDP-induced nephrotoxicity. Also, alterations in the how kidneys of diabetics deal with the renal excretion of Pt and reduction of its accumulation in kidney tissue are not excluded.
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Najjar et al. (2001) studied Cisplatin-induced nephrotoxicity. Streptozotocin-induced diabetes vs. Nondiabetic rabbits was evaluated on Pharmacokinetics of plasma platinum levels and indices of nephrotoxicity (serum creatinine, urea, and albumin) (p=<0.001). The diabetic state protected against cisplatin-induced nephrotoxicity in rabbits, with nondiabetic controls exhibiting significantly higher serum creatinine and urea levels (p < 0.001).
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