Stability of a cisplatin-chondroitin sulfate A complex in plasma and kidney in terms of protein binding

To assess the stability of a cisplatin (CDDP) complex prepared with chondro itin sulfate A (CSA) relative to protein binding in the circulation and kid ney, a trichloroacetic acid (TCA) precipitation method was developed to mea sure the protein-unbound species of CDDP and the CDDP-CSA complex in plasma and kidney homogenates. The total and unbound drug concentrations were det ermined up to 3 h following a 2 mg/kg bolus injection of CDDP or CDDP-CSA c omplex to rats. The stability against plasma binding was evaluated by a det ermination of the area under concentration-time curve from time 0 to infini te time (AUC((0-infinity))); the ratio of unbound drug AUC((0-infinity)) to total drug AUC((0-infinity)) was employed to estimate the availability of the unbound drug in the circulation. The results showed that a competitive reaction to platinum existed between plasma protein and the CDDP-CSA comple x, but the complex accounted for more than 60% of the protein-unbound speci es for a dosage, compared to 30% obtained by an administration of uncomplex ed CDDP. The tissue binding kinetics in kidney for CDDP and the CDDP-CSA co mplex was investigated by the use of homogenates. The binding rate constant s of CDDP and CDDP-CSA in a kidney homogenate were 0.0040 min(-1) and 0.001 4 min(-1), respectively. The results indicate that the CDDP-CSA complex cou ld effectively retard the binding of CDDP to protein in the kidney. These d ata provide evidence that endogenous protein is able to compete for platinu m from the CDDP-CSA complex, but the complex effectively retarded the prote in binding reaction with CDDP in plasma and kidney as compared to native CD DP, which has the potential for reducing the accumulation of CDDP in plasma and kidney.