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Basken NE, Mathias CJ, Green MA: Elucidation of the human serum albumin (HSA) binding site for the Cu-PTSM and Cu-ATSM radiopharmaceuticals. J Pharm Sci. 2009 Jun;98(6):2170-9.
The Cu-PTSM (pyruvaldehyde bis (N (4)-methylthiosemicarbazonato) copper (II)) 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 [(64) Cu] Cu-PTSM and [(64) Cu] Cu-ATSM from HSA. At 8:1 warfarin:HSA mole ratios, free [(64) Cu] Cu-PTSM and [(64) Cu] Cu-ATSM levels increased 300-500%. This was in contrast to solutions containing ibuprofen, a site IIIA drug; no increase in free [(64) Cu] Cu-PTSM or [(64) Cu] 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, [(64) Cu] 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. |
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