NDLI: Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Content Provider	PubMed Central
Author	Levin, Andrew D. Neda, Vukmirovic Hwang, Chao-wei Edelman, Elazer R.
Copyright Year	2004
Abstract	Endovascular drug-eluting stents have changed the practice of medicine, and yet it is unclear how they so dramatically reduce restenosis and how to distinguish between the different formulations available. Biological drug potency is not the sole determinant of biological effect. Physicochemical drug properties also play important roles. Historically, two classes of therapeutic compounds emerged: hydrophobic drugs, which are retained within tissue and have dramatic effects, and hydrophilic drugs, which are rapidly cleared and ineffective. Researchers are now questioning whether individual properties of different drugs beyond lipid avidity can further distinguish arterial transport and distribution. In bovine internal carotid segments, tissue-loading profiles for hydrophobic paclitaxel and rapamycin are indistinguishable, reaching load steady state after 2 days. Hydrophilic dextran reaches equilibrium in several hours at levels no higher than surrounding solution concentrations. Both paclitaxel and rapamycin bind to the artery at 30–40 times bulk concentration. Competitive binding assays confirm binding to specific tissue elements. Most importantly, transmural drug distribution profiles are markedly different for the two compounds, reflecting, perhaps, different modes of binding. Rapamycin, which binds specifically to FKBP12 binding protein, distributes evenly through the artery, whereas paclitaxel, which binds specifically to microtubules, remains primarily in the subintimal space. The data demonstrate that binding of rapamycin and paclitaxel to specific intracellular proteins plays an essential role in determining arterial transport and distribution and in distinguishing one compound from another. These results offer further insight into the mechanism of local drug delivery and the specific use of existing drug-eluting stent formulations.
Related Links	http://dx.doi.org/10.1073/pnas.0400918101
Ending Page	9467
Page Count	5
Starting Page	9463
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	101
Language	English
Publisher	National Academy of Sciences
Publisher Date	2004-06-22
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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