Dc. Thompson et al., ORGAN-SPECIFIC BIOTRANSFORMATION OF ORMAPLATIN IN THE FISCHER-344 RAT, Cancer chemotherapy and pharmacology, 36(5), 1995, pp. 439-447
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;