Dithiocarbamate-induced biliary platinum excretion and the control of cis-platinum nephrotoxicity.
Treatment with any one of six different dithiocarbamates subsequent to the administration of cis-platinum (CDDP) is shown to promote the biliary excretion of platinum. The administration of the most effective of these compounds, sodium diethyldithiocarbamate (DDTC) at 1.57 mmol/kg, led to a 30-fold increase in the biliary excretion of platinum. For the other dithiocarbamates investigated, a similar dosage led to increases ranging from approximately 5-fold for sodium iminodiacetic acid dithiocarbamate, to 26-fold for sodium sarcosine dithiocarbamate. The presence of alkyl groups on the nitrogen of the dithiocarbamate increased the effectiveness of the compounds. There is no increase in the platinum levels of the brain when DDTC is used in this manner. A histopathological evaluation of the kidneys of rats given 15 mg CDDP/kg in 6.3% saline with and without the use of dithiocarbamates for renal protection shows significant additional protection due to the use of the dithiocarbamates. Dithiocarbamates given at an appropriate dosing schedule can lead to a significant reduction in the renal damage which is revealed by microphotographs. It is suggested that part of the renal protection obtained by the use of dithiocarbamates may be due to this shift of platinum excretion to the bile which obviates additional renal exposure to platinum. It was also found that the simultaneous injection of a dithiocarbamate with the cis-platinum has no obvious effect on the anti-cancer action of cis-platinum against the Walker 256 carcinosarcoma in rats.
Basinger
M A
MA
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Jones
M M
MM
Gilbreath
S G
SG
Walker
E M
EM
Fody
E P
EP
Mayhue
M A
MA
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D004050:Ditiocarb / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D010984:Platinum / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D010984:Platinum; D004050:Ditiocarb; D002945:Cisplatin