Elucidation of the Human Serum Albumin (HSA) Binding Site for the Cu-PTSM and Cu-ATSM Radiopharmaceuticals

被引:29
作者
Basken, Nathan E. [1 ]
Mathias, Carla J. [1 ]
Green, Mark A. [1 ]
机构
[1] Purdue Univ, Dept Ind & Phys Pharm, Div Nucl Pharm, W Lafayette, IN 47907 USA
关键词
protein binding; albumin; distribution; PET; preclinical pharmacokinetics; POSITRON EMISSION TOMOGRAPHY; COPPER(II) BIS(THIOSEMICARBAZONE) RADIOPHARMACEUTICALS; REGIONAL MYOCARDIAL PERFUSION; DRUG-BINDING; BLOOD-FLOW; FATTY-ACIDS; L-TRYPTOPHAN; PET; COPPER-62-PTSM; SPECIFICITY;
D O I
10.1002/jps.21570
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The Cu-PTSM (pyruvaldehydebis(N-4-inethylthiosemicarbazonato)copper(11)) and Cu-ATSM (diacetyl bis(N-4-methylthiosemicarbazonato)copper(II)) radiopharmaceuticals exhibit strong, species-dependent binding to human serum albumin (HSA), while Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)) appears to only exhibit nonspecific binding to human and animal serum albumins. This study examines the structural basis for HSA binding of Cu-PTSM and Cu-ATSM via competition with drugs having known albumin binding sites. Warfarin, furosemide, ibuprofen, phenylbutazone, benzylpenicillin, and cephmandole were added to HSA solutions at drug:HSA mole ratios from 0 to 8:1, followed by quantification of radiopharmaceutical binding to HSA by ultrafiltration. Warfarin, a site IIA drug, progressively displaced both [Cu-64] Cu-PTSM and [Cu-64]Cu-ATSM from HSA. At 8:1 warfarin:HSA mole ratios, free [Cu-64]Cu-PTSM and [Cu-64]Cu-ATSM levels increased 300-500%. This was in contrast to solutions containing ibuprofen, a site IIIA drug; no increase in free [Cu-64]Cu-PTSM or [Cu-64]Cu-ATSM was observed except at high ibuprofen:HSA ratios, where secondary ibuprofen binding to the IIA site may cause modest radiopharmaceutical displacement. By contrast, and consistent with earlier findings suggesting Cu-ETS exhibits only nonspecific associations, [Cu-64]Cu-ETS binding to HSA was unaffected by the addition of drugs that bind in either site. We conclude that the species-dependence of Cu-PTSM and Cu-ATSM albumin binding arises from interaction(s) with the IIA site of HSA. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2170-2179, 2009
引用
收藏
页码:2170 / 2179
页数:10
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