Synthesis and Physicochemical Characterization of a Diethyl Ester Prodrug of DTPA and Its Investigation as an Oral Decorporation Agent in Rats.
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 mass casualty situation. Here, the diethyl ester of DTPA, named C2E2, is investigated for potential as an oral treatment for internal radionuclide contamination. C2E2 was synthesized and characterized using NMR, MS, and elemental analysis. The physiochemical properties of solubility, lipophilicity, and stability were investigated in order to predict its oral bioavailability. Finally, an animal efficacy study was conducted in Sprague Dawley rats pre-contaminated by intramuscular injection with (241)Am(NO3)3 to establish effectiveness of the therapy via the oral route. Synthesis of C2E2 yielded a crystalline powder with high solubility and improved lipophilicity over DTPA. The ester was stable in both simulated gastric and intestinal fluids over the anticipated time course of absorption. Capsules containing C2E2 were demonstrated to be stable for 12 months under accelerated stability conditions. After a single dose, C2E2 enhanced the elimination of (241)Am in a dose-dependent manner. Significant improvement was seen in both total (241)Am decorporation and reduction of (241)Am liver and skeletal burden. C2E2 was concluded to be effective when orally administered to (241)Am-contaminated rats. It may therefore have potential for medical countermeasure in treating humans contaminated with (241)Am or other transuranic elements. An oral capsule or powder for reconstitution may be suitable formulations for future development based on the physiochemical properties and anticipated dose required for efficacy.
UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, 125 Mason Farm Road, CB #7362, Chapel Hill, NC, 27599-7362, USA.
James E
JE
Huckle
UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, 125 Mason Farm Road, CB #7362, Chapel Hill, NC, 27599-7362, USA.
Matthew P
MP
Sadgrove
UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, 125 Mason Farm Road, CB #7362, Chapel Hill, NC, 27599-7362, USA.
Marina G D
MG
Leed
UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, 125 Mason Farm Road, CB #7362, Chapel Hill, NC, 27599-7362, USA.
Yu-Tsai
YT
Yang
UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, 125 Mason Farm Road, CB #7362, Chapel Hill, NC, 27599-7362, USA.
Russell J
RJ
Mumper
School of Medicine, Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Richard C
RC
Semelka
UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, 125 Mason Farm Road, CB #7362, Chapel Hill, NC, 27599-7362, USA. mjay@unc.edu.
Michael
M
Jay
D000576:Americium / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002214:Capsules; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D007273:Injections, Intramuscular; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D018482:Muscle, Skeletal / Q000378:metabolism; D004369:Pentetic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D002214:Capsules; D002614:Chelating Agents; D011355:Prodrugs; D004369:Pentetic Acid; D000576:Americium
oral drug delivery; physicochemical properties; pre-formulation; prodrugs