Role of plasma protein binding in brain drug delivery

描述（由申请人提供）：药物递送至脑受到血脑屏障（BBB）的限制（即，神经血管单位），其显著影响许多中枢神经系统（CNS）疾病的治疗。在限制脑药物递送的各种BBB因素中，最不为人所知的因素之一是血浆蛋白结合的贡献，其涉及脑血流、脑毛细血管糖萼和质膜以及毛细血管循环中的游离和结合药物浓度之间的复杂相互作用。大多数药物与血浆蛋白结合显著：约一半结合90%或更多。对于一些人来说，血浆蛋白结合显著降低了大脑的摄取和分布，而对于其他人来说几乎没有影响。绝大多数血脑屏障药物转运研究报告的脑摄取量大于基于血浆中药物游离分数的脑摄取量，并表明在毛细血管循环中发生特殊相互作用，导致体内“解离增强”。净效应是，这阻碍了在药物开发和临床分析中对CNS药物渗透的理解和预测。这项资助的主要假设是，许多药物的脑摄取可以使用修改后的Crone-Renkin模型来预测，该模型除了自由药物摄取和与脑的交换外，还将药物解离和重新结合到脑毛细血管中的血浆蛋白。这一假设将通过四个具体目标来实现：（1）使用仔细控制的原位大鼠脑灌注技术证实，对于许多药物，可以基于四个容易确定的参数-动脉输入药物浓度，动脉输入中药物的游离分数（FU），游离（未结合）药物的表观BBB渗透性-表面积乘积（PSU）和通过脑血管系统的流体流速（F）;（二）评价药物解离和与血浆蛋白再结合的速率及其对表现出高毛细血管密度的药物的初始药物脑摄取的影响。以限定的流速提取;（3）使用灌注技术显示血浆蛋白结合直接影响药物在脑中的稳态分布;和（4）使用Nagase白蛋白敲除大鼠验证这种相同的关系在体内成立，并且稳态下的脑药物浓度最终由血浆游离药物浓度和脑药物分布体积驱动。这项研究将提供一种新的机制，以区分药物，表现出限制性与非限制性血浆蛋白结合作用的脑摄取，将提供一个合理的手段，根据中枢神经系统药物给药的药物，结合显着的血浆蛋白，并将有助于在中枢神经系统药物开发中选择最佳的大脑交付的代理。这项工作对公共卫生的至关重要性在于，它将提高我们预测和鉴定穿过BBB用于治疗CNS疾病的新药物的能力。

DESCRIPTION (provided by applicant): Drug delivery to brain is limited by the blood-brain barrier (BBB) (i.e., neurovascular unit) which markedly impacts treatment for many central nervous system (CNS) diseases. Of the various BBB factors that limit brain drug delivery, one of the least well understood is the contribution of plasma protein binding, which involves a complex interplay between brain blood flow, the brain capillary glycocalyx and plasma membrane, and the free and bound drug concentrations in the capillary circulation. Most drugs bind significantly to plasma proteins: approximately half bind 90% or more. For some, plasma protein binding dramatically reduces brain uptake and distribution, whereas for others there is little or no effect. The great majority of BBB drug transport studies report greater brain uptake than can be accounted for based upon the free Fraction of drug in plasma and have suggested that special interactions occur in the capillary circulation leading to "enhanced dissociation" in vivo. The net effect is that this has impeded understanding and prediction of CNS drug penetration in drug development and clinical analysis. The primary hypothesis of this grant is that brain uptake for many drugs can be predicted using a modified Crone-Renkin model that incorporates drug dissociation and rebinding to plasma proteins in the brain capillary in addition to free drug uptake and exchange with brain. This hypothesis will be pursued through four specific aims: (1) to confirm using a carefully controlled in situ rat brain perfusion technique that initial, unidirectional drug uptake into brain can be predicted for many drugs with a simple model based upon four readily determined parameters - the arterial input drug concentration, the free fraction (fu) of drug in the arterial input, the apparent BBB permeability-surface area product (PSU) to free (unbound) drug, and the flow rate of fluid through the brain vasculature (F); (2) to evaluate the rates of drug dissociation and rebinding to plasma protein and their influence on initial drug uptake into brain for drugs that exhibit high capillary extraction at defined flow rate; (3) to show using the perfusion technique that plasma protein binding directly affects the steady state distribution of drug in brain; and (4) to validate using the Nagase albumin knockout rat that this same relationship holds in vivo and that brain drug concentration at steady state is driven ultimately by the plasma free drug concentration and the brain drug distribution volume. This research will provide a novel mechanism to distinguish drugs that exhibit restrictive vs nonrestrictive plasma protein binding effects on brain uptake, will provide a rational means upon which to base CNS drug-dosing for agents that bind significantly to plasma proteins, and will assist in selection of agents with optimal brain delivery in CNS drug development. The critical importance of this work to public health is that it will improve our ability to readily predict and identify new drug agents that cross the BBB for the treatment of CNS diseases.