Orally Administered DTPA Penta-Ethyl Ester for the Decorporation of Inhaled 241Am

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 [14C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared to 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 241Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of 241Am 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.

Interspecies Differences in the Metabolism of a Multiester Prodrug by Carboxylesterases

“…C2E5, a lipophilic compound with a CLogP value of 4.7, was hydrolyzed by recombinant protein CES1 and CES2 7 . Hydrolysis of C2E5 by CES1 was higher than CES2 at an enzyme concentration of 1mg/ml (Fig.…”

“…The five added ester moieties greatly increase the lipophilicity of DTPA, which is measured by increased CLogP. (CLogP of -2.7 for DTPA in contrast to ClogP of 4.7 to C2E5) Studies in rats confirmed that C2E5 shows enhanced oral bioavailability compared to DTPA, with extensive but incomplete metabolism 7 and can elicit effective radionuclide decorporation following oral 8 and transdermal delivery 9 . Together, these findings suggest that this prodrug may be a useful and effective alternative treatment to DTPA.…”

Orally administered DTPA di-ethyl ester for decorporation of241Am in dogs: Assessment of safety and efficacy in an inhalation-contamination model

“…The liver, spleen, kidneys, lungs and both femurs were among the tissues collected and analyzed for radioactivity. Samples were thermally and chemically processed as previously described (Sueda et al, 2014), placed into 20-mL scintillation vials and the gamma pulse height from 241 Am was analyzed in a gamma counter (2480 Wizard 2 Gamma Counter, Perkin Elmer, Waltham, MA, USA).…”

“…These were the penta-ethyl and di-ethyl esters of DTPA, referred to as C2E5 and C2E2, respectively. C2E5 was shown to effectively decorporate 241 Am in a wound-contamination animal model (Sueda et al, 2012), (Sueda, 2014), but its unfavorable pharmaceutical properties and concerns related to its hepatotoxicity caused us to focus our efforts on C2E2.…”

The Impact of Time on Decorporation Efficacy After a “Dirty Bomb” Attack Studied by Simulation

“…Thus, shortly after injection DTPA is in a large excess (factor 10 4 -10 5 ) compared to plutonium ions. The binding constant of DTPA for tetravalent plutonium has been reported to be about 10 30 (log K = 29.5) [26] and 10 23 at physiological conditions (log K = 23.4) [27]. Since the chelating agent is in vast access of the radionuclide and has high binding affinity, we can reasonably assume that shortly after the injection of 1 g DTPA, virtually all of the plutonium present in the central compartment is bound at the activities studied in this paper.…”