Pharmacological properties of orally available, amphipathic polyaminocarboxylic acid chelators for actinide decorporation.
Pharmacological properties of orally available, amphipathic polyaminocarboxylic acid chelators for actinide decorporation.
复制标题
用于锕系元素修饰的口服两亲性聚氨基羧酸螯合剂的药理学特性。
DOI：
10.1097/hp.0b013e3181bfb99b
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发表时间：
2010
期刊：
影响因子：
2.2
通讯作者：
Bowman,BethM
中科院分区：
文献类型：
--
作者：
Miller,ScottC;Wang,Xuli;Bowman,BethM
常用的水溶性聚氨基羧酸（PACA）螯合剂，例如EDTA和DTPA，由于其生物利用度较差，需要静脉或皮下给药。通过添加改变两亲特性的不同长度的烷基侧链，可以提高 PACA 的生物利用度。口服两亲性三亚乙基四胺五乙酸（TT）化合物对于钚和镅的脱除是有效的。对两亲性 TT 螯合剂的合成、功效、结合亲和力和一些初始药代动力学特性进行了综述。 14 C标记的C 12 TT 和C 22 TT 螯合剂可以很好地从肠道吸收，并且具有大量的胆汁/粪便排泄途径，这与DTPA不同，DTPA主要通过尿液排泄。全身保留时间随着亲脂性的增加而增加。中子诱导放射自显影研究表明，口服螯合剂可以显着抑制 239 Pu 在骨骼组织中的重新分布。总之，基于 TT 的两亲性螯合剂具有良好的生物利用度，具有显着的胆汁排泄途径，已证明对镅和钚具有功效，因此是进一步开发的良好候选者。此外，一些药理学特性可以通过改变烷基侧链的长度来控制，这对于某些金属和放射性核素的修饰可能具有一些优势。
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. 14 C-labeled C 12 TT and C 22 TT 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 239 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.