C2E2: An Orally Administered Radionuclide Decorporation Agent Public Deposited

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  • March 19, 2019
  • Huckle, James
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
  • The increasing threats of nuclear terrorism have made the development of medical countermeasures a priority for international security. Injectable formulations of diethylenetriaminepentaacetic acid (DTPA) have been approved by the FDA, however an oral formulation is more amenable in a situation involving mass casualties. The overall objective of this thesis is to synthesize and characterize the di-ethyl ester of DTPA, named C2E2, and assess the orally bioavailability and radionuclide decorporation efficacy. The first specific aim investigates the physiochemical properties of C2E2. The solubility, lipophilicity and pKa's were determined. C2E2 was shown to have high aqueous solubility and lipophilicity was moderately increased over DTPA. The americium binding constant for C2E2 was also determined and shown to be higher than that of the plasma proteins, suggesting that C2E2 would retain the ability to chelate americium in the plasma despite having a lower coordination number than DTPA. Secondly, both the stability of C2E2 prior to absorption and within the plasma was investigated. Single dose pharmacokinetics in Sprague-Dawley rats demonstrated that C2E2 was the predominant form in plasma after administration along with lower levels of the mono-ester metabolite and DTPA. The oral bioavailability was determined as 29% in Sprague-Dawley rats compared to that of 5% for DTPA. The third aim evaluated both the toxicity and oral efficacy of C2E2 in rats and dogs. Oral dose-range finding toxicology studies were performed to identify no-observed-adverse-effect-levels (NOAEL). Single and multiple dose decorporation efficiency of C2E2 was determined when administered 24 hours post-contamination in rats with an intramuscular wound model with <super>241</super>Am-nitrate. A single dose decorporation efficiency study was performed in dogs with contamination of <super>241</super>Am-nitrate via inhalation. Overall C2E2 was synthesized and shown to have improved oral absorption over DTPA and retained the ability to chelate americium from the plasma. Oral administration of C2E2 exhibited low toxicity, a simple metabolic pathway and enhanced <super>241</super>Am decorporation over control. Based on this research this DTPA analog appears to be an effective orally-administered medical countermeasure for treating individuals contaminated with transuranic elements.
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Rights statement
  • In Copyright
  • Batrakova, Elena
  • Parr, Alan
  • Jay, Michael
  • Thakker, Dhiren
  • Zamboni, William
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
Place of publication
  • Chapel Hill, NC
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