Reaction kinetics of cisplatin and its monoaquated species with the (potential) renal protecting agents (di)mesna and thiosulfate - Estimation of the effect of protecting agents on the plasma and peritoneal AUCs of CDDP

Using simple kinetic modelling, we estimated the effect of nucleophilic (renal) protecting agents (thiosulfate, mesna, diethyldithiocarbamate) on the half-life and the area under the concentration-time curve (AUC) of cis-diamminedichloroplatinum(II) (CDDP) in plasma and peritoneum. Our basic assumptions were that (a) under non-protecting conditions, the elimination of intact CDDP from plasma and peritoneum is a first-order process determined by the elimination-rate constant (k), and (b) under conditions of renal protection, the elimination of CDDP is a first-order process determined by k_CDDP,P=k_CDDP+k_N.[N], with k_CDDP,P representing k_CDDP under conditions of protection; k_N, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration on N. Half-lives under conditions of protection were 0.693/k_CDDP,P. AUCs were obatained by integration of the first-order equations. The inactivation-indicating parameter was defined as being the ratio of the AUC under protecting conditions to the AUC under non-protecting conditions (R_inact). R_inact is approximately given by k_CDDP/k_CDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m^-2 h), the estimates of R_inact were 0.61 in plasma and 0.7 in the peritoneal cavity for i.p. injected CDDP and 0.87 in plasma for i.v. CDDP, indicating inactivation of CDDP under such conditions. Estimates of R_inact were 0.84 or 0.96 in plasma and 0.87 in the peritoneal cavity for supposed conditions of renal protection by systemic mesna (4.4 g m^-2 h), suggesting only minor inactivation of i.p. or i.v. injected CDDP under such conditions. Under reported conditions of protection achieved with 4.4 g m^-2 h systemic diethyldithiocarbamate (DDTC), R_inact was >0.65 or 0.87 in plasma and >0.75 in the peritoneal cativy for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.