Cisplatin pharmacokinetics and its nephrotoxicity in diabetic rabbits

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 ultrafilterab le and total plasma platinum (Pt) levels. Methods: Two groups of age-matche d male New Zealand white rabbits were used; the first group consisted of ra bbits with streptozotocin-induced diabetes (single i.v. bolus dose of strpe tozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of n ondiabetic rabbits treated with the same volume of citrate buffer. Both gro ups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after i nduction of the diabetic state in the first group. The plasma Pt levels wer e followed for 4 h after CDDP administration, in which the free ultrafilter able and total plasma Pt concentrations were determined by atomic absorptio n spectrometry. The pharmacokinetic parameters of free ultrafilterable plas ma Pt were determined using a noncompartment pharmacokinetic model of analy sis. 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 contro l nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher th an 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 nondiabe tic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in c omparison with the diabetic group. Conclusions: These findings might sugges t that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug f ollow-up period. It could be anticipated that the rapid decline in the tota l 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 nephrotoxicit y. Also, alterations in the how kidneys of diabetics deal with the renal ex cretion of Pt and reduction of its accumulation in kidney tissue are not ex cluded. Copyright (C) 2001 S. Karger AG, Basel.