Pharmacological properties of orally available, amphipathic polyaminocarboxylic acid chelators for actinide decorporation.
Commonly used water-soluble polyaminocarboxylic acid (PACA) chelators, such as EDTA and DTPA, require intravenous or subcutaneous administration due to their poor bioavailability. The bioavailability of PACAs can be improved by the addition of differing lengths of alkyl side chains that alter amphipathic properties. Orally administered amphipathic triethylenetetramine pentaacetic acid (TT) compounds are efficacious for decorporation of plutonium and americium. The synthesis, efficacy, binding affinities, and some initial pharmacokinetics properties of amphipathic TT chelators are reviewed. C-labeled C12TT and C22TT chelators are reasonably well absorbed from the intestine and have a substantial biliary/fecal excretion pathway, unlike DTPA, which is mostly excreted in the urine. Whole body retention times are increased as a function of increasing lipophilicity. Neutron-induced autoradiography studies demonstrate that the oral administration of the chelators can substantially inhibit the redistribution of Pu in skeletal tissues. In summary, amphipathic TT-based chelators have favorable bioavailability, have a significant biliary excretion pathway, have demonstrated efficacy for americium and plutonium, and are thus good candidates for further development. Furthermore, some of the pharmacological properties can be manipulated by changing the lengths of the alkyl side chains and this may have some advantage for decorporation of certain metals and radionuclides.
Miller
Scott C
SC
Division of Radiobiology, University of Utah, Salt Lake City, UT 84108, USA. scott.miller@hsc.utah.edu
Wang
Xuli
X
Bowman
Beth M
BM
D000085:Acetates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000284:Administration, Oral; D000576:Americium / Q000493:pharmacokinetics* / Q000633:toxicity; D001345:Autoradiography; D001682:Biological Availability; D002250:Carbon Radioisotopes; D002614:Chelating Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003666:Decontamination / Q000379:methods*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D004369:Pentetic Acid / Q000737:chemistry / Q000494:pharmacology; D011005:Plutonium / Q000493:pharmacokinetics* / Q000633:toxicity; D014266:Trientine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000085:Acetates; D002250:Carbon Radioisotopes; D002614:Chelating Agents; C076893:docosyl-triethylenetetraminepentaacetic acid; D011005:Plutonium; D004369:Pentetic Acid; D014266:Trientine; D000576:Americium