Effects of diethyldithiocarbamate (DDTC) on the plasma biotransformations of tetrachloro(d,l-trans)-1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) in Fischer 344 rats.
We have studied the effects of diethyldithiocarbamate (DDTC) on the biotransformations of toxic doses of tetrachloro (d,l-trans)1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) in Fischer 344 rats. In animals not treated with DDTC, tetraplatin was rapidly converted to dichloro(d,l-trans)1,2-diaminocyclohexaneplatinum(II) [PtCl2(dach)]. Subsequent biotransformations included the transient formation of the (d,l-trans)1,2-diaminocyclohexane-aquachloroplatinum(II) [Pt(H2O)(Cl)(dach)]+ complex, followed by formation of the platinum (Pt)-methionine and either Pt-cysteine or Pt-ornithine complexes. Significant amounts of free (d,l-trans) 1,2-diaminocyclohexane (dach) were observed in plasma as a result of intracellular trans-labilization reactions. DDTC caused a marked decrease in both total and protein-bound platinum in the circulation. A significant increase in the plasma concentration of free dach was also observed as a result of formation of the Pt(DDTC)2 complex. Some of the free dach could have arisen from intracellular reactions with DDTC, but the displacement of platinum from plasma proteins was more than sufficient to account for the increase in free dach in the circulation. DDTC treatment also decreased plasma concentrations of tetraplatin, PtCl2(dach), [Pt(H2O)(Cl) (dach)]+, the Pt-methionine complex, and one unidentified biotransformation product, but had no effect on the Pt-cysteine (or Pt-ornithine) complex. These effects of DDTC on protein-bound platinum and low-molecular-weight biotransformation products in plasma may contribute to the decrease in tetraplatin toxicity seen in DDTC-treated rats.
Carfagna
P F
PF
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill 27599.
Wyrick
S D
SD
Holbrook
D J
DJ
Chaney
S G
SG
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood*; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004050:Ditiocarb / Q000494:pharmacology*; D008297:Male; D009944:Organoplatinum Compounds / Q000097:blood*; D051381:Rats; D011916:Rats, Inbred F344; D014316:Tritium
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D014316:Tritium; D004050:Ditiocarb; C049777:ormaplatin