Effect of Chemoprotectors on the Toxicity and Biotransformation Products of Tetraplatin in the Fischer 344 Rat
Public Deposited- Last Modified
- February 28, 2019
- Creator
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Carfagna, Patrick Francis
- Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
- Abstract
- The efficacy of sodium diethyldithiocarbamate (DDTC), S-2(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) and sodium selenite in reducing the toxicity of the second-generation platinum compound tetrachloro(d,1-trans)1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) was investigated. These three chemoprotectors were chosen based on their ability to reduce cisplatin toxicity. The dose-limiting factors with tetraplatin administration are myelosuppression, gastrointestinal toxicity and nephrotoxicity. In the toxicity studies DDTC and WR-2721 were effective in reducing nephrotoxicity and gastrointestinal toxicity (as measured by blood urea nitrogen, creatinine and histopathological examination), but only DDTC was able to reduce the myelosuppressive effects of tetraplatin (as measured by white blood cells, platelets, lymphocytes and histopathological examination). Sodium selenite was ineffective in protecting against any of the tetraplatin-associated toxicities. Subsequent to the toxicity studies, tetraplatin pharmacokinetic and biotransformation product studies in the presence of DDTC were performed. When tetraplatin was administered alone, 90% of the platinum in plasma was protein-bound after 3 hr and approximately nine different biotransformation products were detected by reverse phase and cation exchange HPLC. This group of biotransformation products included a monoaguamonochloro species, trans-1,2-diaminocyclohexanedichloroplatinum(II) (PtCl2(trans-dach)), a mixture of methionine-platinum complexes, free trans-1,2-diaminocyclohexane (trans-dach) and unmetabolized tetraplatin. DDTC administered at 0.5 hr after tetraplatin injection resulted in significant changes in the platinum pharmacokinetic profiles and the tetraplatin biotransformation products. Only 60% of the platinum was protein-bound 3 hr after tetraplatin administration (2.5 hr after DDTC) resulting in a substantial increase in free platinum. Additionally, the free trans-dach dramatically increased after DDTC administration, while the methionine-platinum complexes were eliminated and the PtCl2(trans-dach) and the monoaguamonochloro species decreased by a factor of 2. These data suggest that the DDTC was displacing the trans-dach moiety from protein-bound platinum by formation of a bis, bidentate platinum(II)-DDTC complex.
- Date of publication
- August 1989
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Chaney, Stephen
- Holbrook, David
- Turner, Alvis G.
- Degree
- Master of Science in Public Health
- Academic concentration
- Environmental Management and Policy
- Degree granting institution
- University of North Carolina at Chapel Hill
- Graduation year
- 1989
- Language
- Deposit record
- ad7e9272-7c4f-43e0-afeb-7a5f2526ad76
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