Orally administered DTPA di-ethyl ester for decorporation of (241)Am in dogs: Assessment of safety and efficacy in an inhalation-contamination model.
OBJECTIVE
Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA)-approved for decorporation of (241)Am; however, an oral product is considered more amenable in a mass casualty situation. The di-ethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination.


METHODS
Single-dose decorporation efficacy of C2E2 administered 24-h post contamination was determined in beagle dogs using a (241)Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test.


RESULTS
Oral administration of C2E2 significantly increased (241)Am elimination over untreated controls and significantly reduced the retention of (241)Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic.


CONCLUSIONS
The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of (241)Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies.
University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Division of Molecular Pharmaceutics , Chapel Hill , NC.
James E
JE
Huckle
Matthew P
MP
Sadgrove
Erik
E
Pacyniak
Marina G D
MG
Leed
Waylon M
WM
Weber
Melanie
M
Doyle-Eisele
Raymond A
RA
Guilmette
Bushra J
BJ
Agha
Robert L
RL
Susick
Russell J
RJ
Mumper
Michael
M
Jay
D000284:Administration, Oral; D000576:Americium / Q000737:chemistry* / Q000302:isolation & purification; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D001239:Inhalation; D020714:Maximum Tolerated Dose; D023421:Models, Animal; D004369:Pentetic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D012449:Safety
D004369:Pentetic Acid; D000576:Americium
Americium; DTPA; alpha emitters; decorporation; radionuclides