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Organ-specific biotransformation of ormaplatin in the Fischer 344 rat

  • Original Article
  • Ormaplatin, Biotransformation, Rats
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Abstract

We examined the intracellular biotransformation products of ormaplatin [(d,l-trans)1,2-diaminocyclohexanetetrachloroplatinum(IV)] (formerly called tetraplatin) in liver, kidney, spleen, small intestine, and plasma of the adult male Fischer 344 rat. Previous studies have established that the rank order of ormaplatin toxicity in Fischer 344 rats is spleen ≈ gastrointestinal tract > kidney ≫ liver. Animals were given tritium-labelled drug i.v. at 12.5 mg/kg, and tissues were harvested 30 min later. The kidney was found to concentrate total and cytosolic platinum to a greater extent than any of the other tissues. The absolute amount of cytosolic platinum, in micrograms per gram tissue, that was irreversibly bound to protein and/or other macromolecules was also greatest in the kidney. However, when the amount bound was expressed as a percentage of the total cytosolic platinum, the kidney was significantly lower than any other tissue. Of the various low molecular mass platinum biotransformation species characterized, by far the most abundant were complexes of platinum with the sulfur-containing molecules cysteine, methionine, and glutathione (GSH). There was more of the methionine complex in the blood plasma than in any of the tissues except for the spleen. No significant differences among the tissues were detected for the dichloro, cysteine, methionine, or the GSH complexes. The tritium-labelled diaminocyclohexane (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 biodistribution nor tissue-specific biotransformation of ormaplatin provides a ready explantation for the tissue specificity of ormaplatin toxicity in Fischer 344 rats. However, in kidney there was much less of the reactive PtCl2(DACH) species than has previously been reported for the corresponding Pt(NH3)2Cl2 species in cisplatin-treated rats. Thus, these data suggest a possible explanation for differences in nephrotoxicity induced by cisplatin versus that by ormaplatin.

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Abbreviations

DACH :

(d,l)Trans-1,2-diaminocyclohexane

PtCl 2 (DACH) :

(d,l)trans-1,2-diaminocyclohexanedichloroplatinum(II)

DDTC :

diethyldithiocarbamate

WR-2721 :

S-2-(3-aminopropylamino)-ethylphosphorothioic acid

HPLC :

high-performance liquid chromatography

RP :

reverse phase chromatography

SCX :

strong cationexchange chromatography

AAS:

flameless atomic absorption spectroscopy

LSC :

liquid scintillation counting

MWCO :

molecular weight cutoff

GSH :

reduced glutathione

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Authors and Affiliations

  1. Curriculum in Toxicology, School of Medicine, University of North Carolina, 27599, Chapel Hill, NC, USA

    D. Charles Thompson, David J. Holbrook & Stephen G. Chaney

  2. Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, 27599-7260, Chapel Hill, NC, USA

    Alexandra Vaisman, Michael K. Sakata, David J. Holbrook & Stephen G. Chaney

  3. Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, 27599, Chapel Hill, NC, USA

    Steven D. Wyriok

Authors
  1. D. Charles Thompson
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  2. Alexandra Vaisman
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  3. Michael K. Sakata
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  4. Steven D. Wyriok
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  5. David J. Holbrook
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  6. Stephen G. Chaney
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Additional information

This work was supported by National Institutes of Health Grants CA55326 and ES07126.

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Charles Thompson, D., Vaisman, A., Sakata, M.K. et al. Organ-specific biotransformation of ormaplatin in the Fischer 344 rat. Cancer Chemother. Pharmacol. 36, 439–447 (1995). https://doi.org/10.1007/BF00686194

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  • DOI: https://doi.org/10.1007/BF00686194

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