Bligh S W, Boyle H A, McEwen A B, Sadler P J, Woodham R H
Department of Chemistry, Birkbeck College, University of London, U.K.
Biochem Pharmacol. 1992 Jan 22;43(2):137-45. doi: 10.1016/0006-2952(92)90270-s.
Reactions of the copper complexes Cu(II)Cl2, [Cu(II)(EDTA)]2-, [Cu(II)2(DIPS)4] and [Cu(I)(DMP)2]+ (where DIPS is 3,5-diisopropylsalicylate and DMP is 2,9-dimethylphenanthroline) with human blood plasma and urine have been studied by 500 MHz 1H NMR spectroscopy, and CD spectroscopy has been used to monitor the transfer of Cu(II) onto albumin in plasma. The rate of transfer of Cu(II) from [Cu(II)(EDTA)]2- onto albumin as measured by CD (T1/2 26 min, 0.5 mM Cu, 21 degrees), was similar to the rate of Cu(II) binding to amino acids and citrate, and to the rate of formation of [Ca(II)(EDTA)]2- in plasma. Reactions of Cu(II)Cl2 and [Cu(II)2(DIPS)4] in plasma followed a similar course, but were more rapid. The latter complex also appeared to give rise to the displacement of lactate from protein binding. Reactions of copper complexes in plasma therefore involve a range of low Mr ligands as well as albumin, and the ligands play a major role in determining the kinetics of the reactions. These factors, as well as the partitioning of both complexes and displaced ligands into lipoproteins, are likely to play important roles in the molecular pharmacology of copper-containing drugs. In urine, His and formate were involved in EDTA and DIPS displacement from their respective copper complexes, and peaks for free DIPS and [Ca(II)(EDTA)]2- were observed. The complex (Cu(I)(DMP)2]+ appeared to be relatively stable in both plasma and urine.
通过500兆赫的1H核磁共振光谱研究了铜配合物Cu(II)Cl2、[Cu(II)(EDTA)]2-、[Cu(II)2(DIPS)4]和[Cu(I)(DMP)2]+（其中DIPS是3,5-二异丙基水杨酸酯，DMP是2,9-二甲基菲咯啉）与人血浆和尿液的反应，并且已使用圆二色光谱来监测血浆中Cu(II)向白蛋白的转移。通过圆二色光谱测量，Cu(II)从[Cu(II)(EDTA)]2-转移到白蛋白上的速率（半衰期26分钟，0.5毫摩尔铜，21摄氏度）与Cu(II)与氨基酸和柠檬酸盐结合的速率以及血浆中[Ca(II)(EDTA)]2-形成的速率相似。血浆中Cu(II)Cl2和[Cu(II)2(DIPS)4]的反应遵循相似的过程，但更快。后一种配合物似乎还导致乳酸从蛋白质结合中被置换出来。因此，血浆中铜配合物的反应涉及一系列低分子量配体以及白蛋白，并且这些配体在决定反应动力学方面起主要作用。这些因素，以及配合物和被置换配体在脂蛋白中的分配，可能在含铜药物的分子药理学中起重要作用。在尿液中，组氨酸和甲酸参与了从各自铜配合物中置换出EDTA和DIPS的过程，并且观察到了游离DIPS和[Ca(II)(EDTA)]2-的峰。配合物(Cu(I)(DMP)2]+在血浆和尿液中似乎都相对稳定。
