Predicting plutonium decorporation efficacy after intravenous administration of DTPA formulations: Study of pharmacokinetic-pharmacodynamic relationships in rats.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
Both liposomal formulations of chelating agents and pharmacokinetic approaches to plutonium decorporation should be helpful in optimising treatment protocols.
Phan
Guillaume
G
CEA, Service de Pharmacologie et d'Immunologie, DSV/DRM, 91191, Gif-sur-Yvette, France.
Le Gall
Béatrice
B
Deverre
Jean-Robert
JR
Fattal
Elias
E
Bénech
Henri
H
D000818:Animals; D019540:Area Under Curve; D002614:Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D006207:Half-Life; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D004369:Pentetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D011005:Plutonium / Q000493:pharmacokinetics* / Q000652:urine; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D002614:Chelating Agents; D004337:Drug Carriers; D008081:Liposomes; D011005:Plutonium; D004369:Pentetic Acid