Decorporation of Aged Americium Deposits by Oral Administration of Lipophilic Polyamino Carboxylic Acids

Article abstract of DOI:10.1021/jm00079a014

Several new powerful chelating agents, suitable for the removal of a variety of certain heavy-metal ions from the body by oral application, have been synthesized and tested.Structurally, these compounds are partially lipophilic polyamino carboxylic acids (PACA).They were synthesized in nonaqueous media from triethylenetetramine (TT) by monoalkylation of a primary amino group, followed by exhaustive carboxymethylation of the remaining amino groups using ethyl bromoacetate and subsequent alkaline hydrolysis of the ester.Compounds were characterized using IR, 1H NMR, 13C NMR, and mass spectrometry.Synthesis and testing of two of these compounds, C12- and C22-triethylenetetraminepentaacetic acid (CnTT), is described in detail.Gel permeation chromatography of a mixture of the PACA and actinide elements have shown these substances to be strong chelating agents similar to EDTA or DTPA.They were capable of removing plutonium from contaminated liver cytosol in vitro.In contrast to their nonlipophilic counterparts EDTA and DTPA, the model substances exhibited appreciable absorption from the intestine and, therefore, can be administered orally.With increasing length of the alkyl chain, the chelons can be directed primarily to the liver, one of the target organs for actinide contamination.In vivo, absorption from the ligated duodenum and jejunum of rats after 2 h was 27percent of the amount introduced.Compared to untreated controls, daily feeding of 200 μmol of the chelons (C12TT or C22TT)/kg of body weight to rats for 10 days reduced the whole body Am by 29percent and 44percent, respectively.Am was eliminated most efficiently from the liver, with a reduction of 71percent and 89percent (p < 0.001).However, the skeletal retention also was reduced by 17percent and 32percent from the femora (p < 0.001) and 20percent and 37percent from the carcass for the C12TT and C22TT compounds, respectively.No weight loss or other obvious signs of blood, kidney, liver, or intestinal toxicity were observed after the 10-day treatment.These new chelators are promising as agents for oral chelation therapy to remove actinides and possibly other elements from body stores.