Comparative effects of diethyldithiocarbamate and N-benzyl-D-glucamine dithiocarbamate on cis-diamminedichloroplatinum-induced toxicity in kidney and gastrointestinal tract in rats.
Sodium diethyldithiocarbamate (DDTC) and sodium N-benzyl-D-glucamine dithiocarbamate (BGD) were compared for their protective effects against cis-diamminedichloroplatinum (DDP)-induced toxicity in kidney and gastrointestinal tract in rats. Rats were injected i.p. with the dithiocarbamates (2.0 mmol kg-1) immediately or 1 h after i.v. injection of DDP (20 mumol kg1). Treatment with BGD immediately or at 1 h after DDP injection effectively prevented the nephrotoxicity of DDP, but administration of DDTC immediately or 1 h after DDP afforded little protection. N-Benzyl-D-glucamine dithiocarbamte significantly reversed the reduction in maltase, sucrase and aminopeptidase activities of jejunal mucosa of rats treated with DDP, whereas treatment with DDTC concurrent with DDP could not reverse the reduction in disaccharidase activity following DDP injection. The platinum concentrations in liver and kidney were significantly decreased by treatment with BGD and DDTC. The treatment with DDTC at 1 h after DDP was more effective on the reduction of platinum concentrations in these tissues than that immediately after DDP. There was no difference between the renal and hepatic concentrations of platinum in two time intervals of BGD. The pharmacokinetic studies indicated that DDTC is more rapidly metabolized than BGD, resulting in larger total clearance and elimination rate constant values. These results reveal that the administration of BGD immediately and at 1 h after DDP can protect against the renal and gastrointestinal toxicities caused by DDP, whereas DDTC afforded little protection, and that the time interval between administration of DDP and DDTC greatly influences its protective effect on DDP-induced toxicity, indicating that the chelation therapy of BGD for DDP is superior to that of DDTC.
Hidaka
S
S
Department of Pharmacy, Miyazaki Medical College Hospital, Japan.
Funakoshi
T
T
Shimada
H
H
Tsuruoka
M
M
Kojima
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000652:urine; D002614:Chelating Agents / Q000494:pharmacology*; D015913:Chelation Therapy; D002945:Cisplatin / Q000633:toxicity*; D004064:Digestive System / Q000737:chemistry / Q000187:drug effects*; D004050:Ditiocarb / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006029:Glycosuria; D007668:Kidney / Q000737:chemistry / Q000187:drug effects*; D008099:Liver / Q000737:chemistry; D008297:Male; D010984:Platinum / Q000032:analysis; D011507:Proteinuria; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013859:Thiocarbamates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002614:Chelating Agents; D013859:Thiocarbamates; D010984:Platinum; D013012:Sorbitol; D004050:Ditiocarb; D001219:Aspartate Aminotransferases; C048763:N-benzylglucamine dithiocarbamate; D002945:Cisplatin