Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel
Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel
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DOI：
10.1073/pnas.0400918101
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发表时间：
2004-06-22
影响因子：
11.1
通讯作者：
Edelman, ER
中科院分区：
文献类型：
--
作者：
Levin, AD;Vukmirovic, N;Edelman, ER
血管内药物洗脱支架改变了医学实践，但尚不清楚它们如何如此显着地减少再狭窄以及如何区分可用的不同配方。生物药物效力并不是生物效应的唯一决定因素。药物的物理化学特性也发挥着重要作用。从历史上看，出现了两类治疗化合物：疏水性药物，其保留在组织内并具有显着的效果；亲水性药物，其被快速清除且无效。研究人员现在质疑，除了脂质亲和力之外，不同药物的个体特性是否可以进一步区分动脉运输和分布。在牛颈内动脉段中，疏水性紫杉醇和雷帕霉素的组织负荷曲线无法区分，2天后达到负荷稳定状态。亲水性右旋糖酐在数小时内达到平衡，其水平不高于周围溶液的浓度。紫杉醇和雷帕霉素均以 30-40 倍体积浓度与动脉结合。竞争性结合测定证实与特定组织成分的结合。最重要的是，两种化合物的透壁药物分布曲线明显不同，这可能反映了不同的结合模式。雷帕霉素与 FKBP12 结合蛋白特异性结合，均匀分布在动脉中，而与微管特异性结合的紫杉醇主要保留在内膜下空间。数据表明，雷帕霉素和紫杉醇与特定细胞内蛋白质的结合在确定动脉转运和分布以及区分一种化合物和另一种化合物方面起着重要作用。这些结果进一步深入了解局部药物输送机制和现有药物洗脱支架配方的具体用途。
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.