Physicochemical characterization of a prodrug of a radionuclide decorporation agent for oral delivery.
Intravenously administered calcium and zinc complexes of diethylenetriaminepentaacetic acid (DTPA) are the agents of choice to treat individuals who have been contaminated with radioactive actinides. However, their use in a mass casualty scenario is hampered by the need for trained personnel to receive treatment. Because DTPA is a highly ionized molecule with permeability-limited bioavailability, the penta-ethyl ester prodrug of DTPA is under evaluation as an orally bioavailable radionuclide decorporation agent. In this work, the physicochemical properties of DTPA penta-ethyl ester were characterized to assess its potential for oral delivery. DTPA penta-ethyl ester was determined to be a low-viscosity liquid with Newtonian flow characteristics. Consistent with the measured pK(a) values, which range from 2.93 to 10.87, this prodrug exhibits pH-dependent solubility and lipophilicity properties that are representative of a weak base and favorable for oral absorption. It is miscible in solvents that are nonpolar to moderately polar and is sufficiently stable to avoid premature hydrolysis during gastrointestinal transit. Therapeutic effects were demonstrated in an initial efficacy study wherein oral treatments of the prodrug were given to rats contaminated with ²⁴¹Am, providing preliminary indications of successful oral delivery. The properties of the prodrug indicate that it is conducive to oral delivery and may offer therapeutic benefits over the standard DTPA therapy following radionuclide contamination.
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Katsuhiko
K
Sueda
Matthew P
MP
Sadgrove
Jonathan M
JM
Fitzsimmons
Michael
M
Jay
D000284:Administration, Oral; D000576:Americium / Q000302:isolation & purification*; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D006868:Hydrolysis; D004369:Pentetic Acid / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014783:Viscosity
D000931:Antidotes; D004952:Esters; D011355:Prodrugs; D004369:Pentetic Acid; D000576:Americium