title: Orally administered DTPA penta-ethyl ester for the decorporation of inhaled (241)Am.
abstract: Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [(14) C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared with a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of (241) Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of (241) Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized.
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, Chapel Hill, North Carolina.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Sueda
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Sadgrove
authors.forename: James E
authors.initials: JE
authors.lastname: Huckle
authors.forename: Marina G D
authors.initials: MG
authors.lastname: Leed
authors.forename: Waylon M
authors.initials: WM
authors.lastname: Weber
authors.forename: Melanie
authors.initials: M
authors.lastname: Doyle-Eisele
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Guilmette
authors.forename: Michael
authors.initials: M
authors.lastname: Jay
mesh_terms: D000284:Administration, Oral; D000336:Aerosols / Q000008:administration & dosage / Q000378:metabolism; D000576:Americium / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D002614:Chelating Agents / Q000008:administration & dosage / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism; D006868:Hydrolysis; D008297:Male; D009566:Nitrates / Q000008:administration & dosage; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism; D011868:Radioisotopes / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D002614:Chelating Agents; D009566:Nitrates; D011355:Prodrugs; D011868:Radioisotopes; C583865:diethylenetriamine pentaacetic acid penta-ethyl ester; D004369:Pentetic Acid; D000576:Americium
keywords: ADME; chelation; oral absorption; pharmacokinetics; prodrugs