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The tissue distribution in BALB/c mice of C-14-labeled JM216, an orally active platinum antitumour compound
P I Bates1, H L Sharma, B A Murrer
1Department of Medical Biophysics, University of Manchester, Medical School, UK.
Abstract:
The ammine/amine platinum(IV) dicarboxylates have been developed as orally active platinum antitumor agents, and one of these, [PtCl2(NH3)(C6H11NH2) (OCOCH3)2] (JM216), is undergoing clinical trials at present. A synthesis method was developed to radiolabel JM216 with carbon 14 at the carboxylate carbon. The labeling efficiency was 92%, and the purity as shown by high-performance liquid chromathography (HPLC) was 96% after recrystallisation. The radiolabeled JM216 was given orally to BALB/c mice and detailed tissue-distribution data were obtained (blood plasma, kidney, liver, spleen, brain, lung, muscle and skin) for time points of 2 h and 2, 6 and 10 days. Comparison of these data with previously reported data for distribution of platinum obtained by atomic absorption spectroscopy has shown distinct differences, especially for the liver and the kidney. This clearly indicates a difference in behaviour between the labeled ligand and the platinum centre, suggesting detachment of the ligand in vivo.
Insights
Radiolabeled platinum(IV) dicarboxylate JM216 was orally administered to mice. Tissue distribution analysis revealed distinct differences between the platinum center and the labeled ligand, suggesting in vivo ligand detachment.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacokinetics
Background:
- Platinum(IV) dicarboxylates are promising orally active anticancer agents.
- JM216, a specific platinum(IV) dicarboxylate, is currently in clinical trials.
- Understanding the in vivo behavior of these agents is crucial for optimizing their efficacy.
Purpose of the Study:
- To develop a method for radiolabeling the platinum(IV) dicarboxylate JM216 with carbon-14.
- To investigate the tissue distribution of radiolabeled JM216 after oral administration in mice.
- To compare the distribution of the radiolabeled ligand with the platinum center to assess in vivo stability.
Main Methods:
- Synthesis of carbon-14 radiolabeled JM216 with high labeling efficiency (92%) and purity (96%).
- Oral administration of radiolabeled JM216 to BALB/c mice.
- Quantification of tissue distribution (blood, kidney, liver, spleen, brain, lung, muscle, skin) at various time points using radiodetection.
Main Results:
- Detailed tissue distribution data were obtained for multiple organs and time points.
- Significant differences in distribution were observed between the radiolabeled ligand and the platinum center, particularly in the liver and kidney.
- These discrepancies suggest that the carboxylate ligand detaches from the platinum core in vivo.
Conclusions:
- The developed radiolabeling method allows for accurate tracking of JM216's fate in vivo.
- Ligand detachment from the platinum(IV) dicarboxylate core occurs in vivo, impacting the drug's distribution and potentially its mechanism of action.
- Further studies are warranted to elucidate the clinical implications of this ligand dissociation.
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