Predicting Plutonium Decorporation Efficacy after Intravenous Administration of DTPA Formulations: Study of Pharmacokinetic–Pharmacodynamic Relationships in Rats
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The objectives of this study were: 1) to assess the relationship between plutonium decorporation (increased excretion and reduced retention in main organs of deposition) induced by intravenous liposome formulations of the chelating agent diethylene triamine pentaacetic acid (DTPA) and its pharmacokinetics, and 2) to model the renal excretion of plutonium after treatment with liposome-encapsulated DTPA in order to predict its efficacy and to optimise treatment schedules.
Materials and Methods
Pharmacokinetic parameters from plasma or urinary data (days 0–16 sample collections) were modelled versus decorporation efficacy, and best correlations were selected for their goodness of fit.
The plutonium decorporation enhancement by DTPA liposomal formulations was well described by logistic models and the best correlation was observed with the area under the DTPA concentration curve of each formulation. The plutonium urinary excretion rates decreased mono-exponentially as a function of time after a single dose and the proposed model allowed a simple determination of the elimination half-life of the Pu–DTPA complex, a reasonably good approximation of the long-term efficacy of the treatments from truncated urinary data.
Both liposomal formulations of chelating agents and pharmacokinetic approaches to plutonium decorporation should be helpful in optimising treatment protocols.
Key wordsDTPA excretion rate liposome PK/PD correlation plutonium decorporation
conventional multilamellar vesicle
- CL-100 nm
conventional liposome sized at around 100 nm
diethylene triamine pentaacetic acid
stealth multi-lamellar vesicle
sterically stabilized (Stealth®) liposome
- SL-100 nm
stealth liposome sized at around 100 nm
The authors acknowledge the scientific committee of the Nuclear Toxicology Programme of the CEA, France for funding.
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