Grants and Contracts Details
The University of Kentucky, in collaboration with ChemPharma International, proposes to develop a prod rug of OTPA that has an oral bioavailability sufficient to achieve plasma levels of OTPA for the decorporation of transuranic compounds. The proposed prodrug approach involves the derivatization of the carboxylate groups of OTPA with non-toxic lipophilic moieties that will enhance its absorption after oral administration, but that will be rapidly cleaved to result in free OTPA in the blood. The objectives of the Phase I proposal are to: (1) Synthesize and chemically characterize nine ester prodrugs of OTPA; (2) Determine their physical-chemical properties (3) Develop suitable formulations for in vitro evaluation and in vivo bioavailability studies; (4) Develop analytical methods for DTPA and selected prodrug(s) in oral formulations and biological fluids; (5) Assess the permeability of prodrugs in a Caco-2 cell model; (6) Conduct in vivo bioavailability studies in rats; (7) Assess the ability of the most promising DTPA prod rug compound(s) to reduce the body burden of 241Am; and (8) Develop formulations of DTPA-prodrug for oral administration suitable for a Phase I clinical study. Phase" will involve large scale animal bioavailability and decorporation studies as well as scale up of the prodrug synthesis and formulated product. The ultimate goal is to identify an effective OTPA prodrug for inclusion in the Strategic National Stockpile.
|Effective start/end date||9/30/05 → 9/30/07|
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