In vitro biotransformations of tetrachloro(d,l-trans)-1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) in rat plasma.

The in vitro biotransformation of tetrachloro(d,l-trans)-1,2,-diaminocyclohexaneplantinum(IV) (tetraplatin) in the plasma of Fischer 344 rats were studied by the two-column high-performance liquid chromatography technique described previously (Mauldin et al., Cancer Res., 48: 5136-5144, 1988). The reduction of tetraplatin to dichloro(d,l-trans)-1,2-diaminocyclohexaneplatinum(II) [PtCl2(dach)] was extremely rapid. From experiments with diluted plasma, it was possible to estimate a t1/2 for tetraplatin of approximately 3 s at 37 degrees C in undiluted plasma. By titrating with N-ethylmaleimide, it was possible to show that sulfhydryl groups were responsible for 70-80% of the total reducing potential of plasma. The rapid reduction of tetraplatin to PtCl2(dach) was followed by slower substitution reactions involving the chloro ligands of PtCl2(dach). The t1/2 for PtCl2(dach) in plasma at 37 degrees C was 1.5 h. The monoaquamonochloro complex was an important biotransformation product at early times, reaching 10 to 12% of the total platinum present from 15 min to 2 h, when it was gradually replaced with more stable biotransformation products. Three major stable biotransformation products accumulated in the plasma. One of these biotransformation products was identified as the Pt(methionine)(dach) complex. The other two were tentatively identified as the Pt(cysteine)(dach) or Pt(ornithine)(dach) complex and the Pt(urea)(dach) or Pt(citrato)(dach) complex on the basis of coelution in two different high-performance liquid chromatography separation systems. These biotransformation products could play a role in tetraplatin effectiveness and/or toxicity.