Orally administered penta-ethyl ester prodrug of DTPA for the decorporation of americium-241

Sueda, Katsuhiko

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March 22, 2019

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Sueda, Katsuhiko
- Affiliation: Eshelman School of Pharmacy

Abstract

Diethylenetriaminepentaacetic acid (DTPA) is an intravenously administered chelating agent that is used to facilitate the elimination of 241Am from contaminated individuals. Despite its long history of use in chelation therapy, its optimal dose has not been clearly established. To evaluate the potential of DTPA to bind 241Am under biological conditions, in vitro binding studies were conducted in rat, beagle, and human plasma. Dose-response curves for DTPA were established, and DTPA was determined to be most efficient in human plasma and least efficient in rat plasma. These results suggest that species differences must be considered when translating the efficacy of DTPA from animals to humans. The oral delivery of DTPA is challenged by its permeability-limited bioavailability, limiting its utility in mass casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester of DTPA was explored. Initial assessments of the prodrug identified favorable physicochemical properties for oral delivery. Consistent with the measured pK?a? values, the prodrug exhibited pH-dependent solubility and lipophilicity of a weak base that is suitable for absorption. Caco-2 permeability assay confirmed the improved epithelial transport of the prodrug over DTPA. From in vitro assessments, the prodrug appeared to be sufficiently stable against premature hydrolysis during gastrointestinal transit. The prodrug was further evaluated in pharmacokinetic, biodistribution, and efficacy studies in rats. A single dose oral administration of the prodrug demonstrated significant absorption over 24 h based on the urinary excretion data. From the urine composition, bioactivation was determined to be extensive but incomplete. Tissue distribution at 12 h was limited primarily to the gastrointestinal tract. A single dose intravenous administration of the prodrug resulted in significant fecal excretion, indicating that biliary clearance is also important to the elimination process. From the pharmacokinetic analysis, the oral administration of the prodrug appeared to be exhibit favorable characteristics for decorporation, including some potential improvements over intravenously administered DTPA. In rats contaminated with 241Am by inhalation, a single dose treatment with the prodrug significantly enhanced decorporation compared to placebo. Overall, DTPA penta-ethyl ester exhibited promising physicochemical, pharmacokinetic, and therapeutic attributes as an orally administered prodrug of DTPA for radionuclide decorporation.

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