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 kCDDP,P = kCDDP+kN.[N], with kCDDP,P representing kCDDP under conditions of protection; kN, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration of N. Half-lives under conditions of protection were 0.693/kCDDP,P. AUCs were obtained 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 (Rinact). Rinact is approximately given by kCDDP/kCDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m-2h), the estimates of Rinact 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 Rinact 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). Rinact was greater than 0.65 or 0.87 in plasma and greater than 0.75 in the peritoneal cavity for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.
Leeuwenkamp
O R
OR
Dept. of Oncology, Free University Hospital, Amsterdam, The Netherlands.
van der Vijgh
W J
WJ
Neijt
J P
JP
Pinedo
H M
HM
D000818:Animals; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics*; D004050:Ditiocarb / Q000494:pharmacology*; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D015080:Mesna / Q000031:analogs & derivatives* / Q000494:pharmacology; D008954:Models, Biological; D010529:Peritoneal Cavity; D013885:Thiosulfates / Q000494:pharmacology*
D013885:Thiosulfates; C027032:2,2'-dithiodiethanesulfonic acid; D004050:Ditiocarb; D015080:Mesna; D002945:Cisplatin