Arterial ultrastructure influences transport of locally delivered drugs
Arterial ultrastructure influences transport of locally delivered drugs
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DOI：
10.1161/01.res.0000016672.26000.9e
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发表时间：
2002-04-19
影响因子：
20.1
通讯作者：
Edelman, ER
中科院分区：
文献类型：
--
作者：
Hwang, CW;Edelman, ER
对调节药物分布的运输力和局部组织结构的不完全了解阻碍了许多器官系统的局部药物治疗。这些问题尤其与动脉有关，在动脉中，基于支架的输送允许对局部定向药物释放进行精细控制。局部给药产生巨大的药物浓度梯度，尽管这些梯度部分来自于运输力，但组织间沉积的差异意味着组织超微结构也发挥着重要作用。我们测量了右旋糖苷(一种类似于肝素的模型亲水性药物)和白蛋白在不同血管床移植的动脉中的平衡药物摄取和渗透扩散系数。我们发现药物分布与几何取向和动脉结缔组织含量有显著差异。与结缔组织鞘平行的药物扩散系数比穿过这些鞘的大一到两个数量级。对于70 kDa以下的药物，这一扩散率差异保持相对恒定，而对于较大的药物，扩散率差异则减小。药物在弹性动脉中的分布也更好，尤其是在较低分子质量的动脉中，进入胸主动脉的转移比进入颈动脉的转移要多66%。因此，动脉药物转运是高度各向异性的，并且依赖于动脉组织的含量。动脉组织的局部成分和几何结构在影响血管药代动力学中的作用可能成为局部血管给药的重要考虑因素。
An incomplete understanding of the transport forces and local tissue structures that modulate drug distribution has hampered local pharmacotherapies in many organ systems. These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release. Local delivery produces tremendous drug concentration gradients and although these are in part derived from transport forces, differences in deposition from tissue to tissue imply that tissue ultrastructure also plays an important role. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (a model hydrophilic drug similar to heparin) and albumin in orthogonal planes in arteries explanted from different vascular beds. We found significant variations in drug distribution with geometric orientation and arterial connective tissue content. Drug diffusivities parallel to the connective tissue sheaths were one to two orders of magnitude greater than across these sheaths. This diffusivity difference remained relatively constant for drugs up to 70 kDa before decreasing for larger drugs. Drugs also distributed better into elastic arteries, especially at lower molecular weights, with almost 66% greater transfer into the thoracic aorta than into the carotid artery. Arterial drug transport is thus highly anisotropic and dependent on arterial tissue content. The role of the local composition and geometric organization of arterial tissue in influencing vascular pharmacokinetics is likely to become a critical consideration for local vascular drug delivery.