Effects of a cisplatin-chondroitin sulfate A complex in reducing the nephrotoxicity of cisplatin

To assess the effects of a macromolecular prodrug in reducing the nephrotox icity of cisplatin (CDDP), chondroitin sulfate A (CSA) with a mean molecula r weight of 23,000 Da was used to form a complex with CDDP, and the pharmac okinetics and toxicology of the resulting complex were examined in rats in comparison with those of CDDP. The total plasma platinum levels and urinary accumulation were determined up to 3 h following a bolus injection of 2 mg /kg. The results of the pharmacokinetic analysis showed that the complex su ppressed the rapid distribution of CDDP, decreased the renal clearance and resulted in over fivefold higher AUC values within 3 h in comparison with C DDP treatment. In addition. the plasma levels of the drug following adminis tration of the complex decreased greatly with time throughout the experimen tal period (3-24 h), whereas a slow elimination was observed following CDDP administration, which was due to the irreversible protein binding of CDDP. The tissue-to-plasma partition ratio at 10 min also indicated that the CDD P-CSA complex controlled the perfusion of CDDP to tissues, especially to th e kidney. The accumulation in various tissues was evaluated at 3 h and 24 h following the injection of 5 mg/kg. Marked differences in renal accumulati on were found within 3 h. Significant reductions in accumulation in the kid ney, lung, muscle and whole blood were found within 24 h of administration of the complex. The renal toxicity of the CDDP-CSA complex was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (Cr) and the ratio o f terminal kidney weight to body weight at doses of 2 mg/kg and 5 mg/kg. Th e complex displayed a much lower nephrotoxicity at 5 mg/kg in comparison to CDDP, and similar results were obtained at 2 mg/kg. This suggests that the complex changed the toxicodynamics of CDDP. Moreover, the anticancer activ ity of the CDDP-CSA complex, tested against SW 4800 human colon cancer cell s and HeLa human cervix cancer cells in vitro, showed no decrease as compar ed with that of free CDDP. We conclude that the CDDP-CSA complex had the sa me activity as the parent drug but showed reduced nephrotoxicity at high do ses of CDDP through an improvement in the pharmacokinetics of CDDP, which r esulted from both the minimization of entry into normal tissues and renal c learance. In addition, it is also possible that different intracellular int eractions in renal cells play a role in protection against the nephrotoxici ty of high doses of CDDP.