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 nephrotoxicity of cisplatin (CDDP), chondroitin sulfate A (CSA) with a mean molecular weight of 23,000 Da was used to form a complex with CDDP, and the pharmacokinetics 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 suppressed the rapid distribution of CDDP, decreased the renal clearance and resulted in over fivefold higher AUC values within 3 h in comparison with CDDP treatment. In addition, the plasma levels of the drug following administration of the complex decreased greatly with time throughout the experimental 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 CDDP-CSA complex controlled the perfusion of CDDP to tissues, especially to the 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 accumulation were found within 3 h. Significant reductions in accumulation in the kidney, 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 of terminal kidney weight to body weight at doses of 2 mg/kg and 5 mg/kg. The 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 activity of the CDDP-CSA complex, tested against SW 4800 human colon cancer cells and HeLa human cervix cancer cells in vitro, showed no decrease as compared with that of free CDDP. We conclude that the CDDP-CSA complex had the same activity as the parent drug but showed reduced nephrotoxicity at high doses of CDDP through an improvement in the pharmacokinetics of CDDP, which resulted from both the minimization of entry into normal tissues and renal clearance. In addition, it is also possible that different intracellular interactions in renal cells play a role in protection against the nephrotoxicity of high doses of CDDP.
Zhang
J S
JS
Faculty of Pharmaceutical Science, Kumamoto University, Japan.
Imai
T
T
Otagiri
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D001806:Blood Urea Nitrogen; D002809:Chondroitin Sulfates / Q000493:pharmacokinetics* / Q000633:toxicity; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D004337:Drug Carriers; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D004337:Drug Carriers; D002809:Chondroitin Sulfates; D003404:Creatinine; D002945:Cisplatin