ORGAN-SPECIFIC BIOTRANSFORMATION OF ORMAPLATIN IN THE FISCHER-344 RAT

We examined the intracellular biotransformation products of ormaplatin ns)1,2-diamino-cyclohexanetetrachloroplatinum(IV)] (formerly called t etraplatin) in liver, kidney, spleen, small intestine, and plasma of t he adult male Fischer 344 rat. Previous studies have established that the rank order of ormaplatin toxicity in Fischer 344 rats is spleen ap proximate to gastrointestinal tract > kidney '' liver. Animals were gi ven tritium-labelled drug i.v. at 12.5 mg/kg, and tissues were harvest ed 30 min later. The kidney was found to concentrate total and cytosol ic platinum to a greater extent than any of the other tissues. The abs olute amount of cytosolic platinum, in micrograms per gram tissue, tha t was irreversibly bound to protein and/or other macromolecules was al so greatest in the kidney. However, when the amount bound was expresse d as a percentage of the total cytosolic platinum, the kidney was sign ificantly lower than any other tissue. Of the various low molecular ma ss platinum biotransformation species characterized, by far the most a bundant were complexes of platinum with the sulfur-containing molecule s cysteine, methionine, and glutathione (GSH). There was more of the m ethionine complex in the blood plasma than in any of the tissues excep t for the spleen. No significant differences among the tissues were de tected for the dichloro, cysteine, methionine, or the GSH complexes. T he tritium-labelled diamino-cyclohexane (DACH) carrier ligand appeared to remain stably bound to the platinum while in the plasma, as there was less free DACH ligand detected in plasma ultrafiltrate than in any tissue ultrafiltrate. Among the tissues, the free DACH levels were in the range of 20% of the radioactivity recovered from the HPLC column and were not significantly different. Consequently, neither biodistrib ution nor tissue-specific biotransformation of ormaplatin provides a r eady explanation for the tissue specificity of ormaplatin toxicity in Fischer 344 rats. However, in kidney there was much less of the reacti ve PtCl2(DACH) species than has previously been reported for the corre sponding Pt(NH3)(2)Cl-2 species in cisplatin-treated rats. Thus, these data suggest a possible explanation for differences in nephrotoxicity induced by cisplatin versus that by ormaplatin;