PDF(Pubmed)
Abstract：
The lack of effective chemotherapeutic agents for the treatment of brain tumors is a serious unmet medical need. This can be attributed, in part, to inadequate delivery through the blood-brain barrier (BBB) and the tumor-cell barrier, both of which have active efflux transporters that can restrict the transport of many potentially effective agents for both primary and metastatic brain tumors. This review briefly summarizes the components and function of the normal BBB with respect to drug penetration into the brain and the alterations in the BBB due to brain tumor that could influence drug delivery. Depending on what is rate-limiting a compound\'s distribution, the limited permeability across the BBB and the subsequent delivery into the tumor cell can be greatly influenced by efflux transporters and these are discussed in some detail. Given these complexities, it is necessary to quantify the extent of brain distribution of the active (unbound) drug to compare across compounds and to inform potential for use against brain tumors. In this regard, the metric, Kp,uu, a brain-to-plasma unbound partition coefficient, is examined and its current use is discussed. However, the extent of active drug delivery is not the only determinant of effective therapy. In addition to Kp,uu, drug potency is an important parameter that should be considered alongside drug delivery in drug discovery and development processes. In other words, to answer the question - How much is enough? - one must consider how much can be delivered with how much needs to be delivered.
摘要：
用于治疗脑肿瘤的有效化学治疗剂的缺乏是严重的未满足的医学需求。这可以归因于，在某种程度上,通过血脑屏障（BBB）和肿瘤细胞屏障的传递不足，两者都具有主动外排转运蛋白，可以限制原发性和转移性脑肿瘤许多潜在有效药物的转运。这篇综述简要概述了正常BBB在药物渗透到大脑中以及由于脑肿瘤而可能影响药物递送的BBB变化方面的成分和功能。根据化合物分布的速率限制，跨BBB的有限通透性和随后递送到肿瘤细胞中可受到外排转运蛋白的极大影响,这些将进行详细讨论。鉴于这些复杂性，有必要量化活性（未结合）药物的脑分布程度，以比较化合物之间的差异，并告知抗脑肿瘤的潜力。在这方面,度量标准，Kp,uu,大脑到血浆的未结合分配系数，进行了检查，并讨论了其当前用途。然而,活性药物递送的程度并不是有效治疗的唯一决定因素。除了Kp,uu,药物效价是一个重要的参数，在药物发现和开发过程中应与药物递送一起考虑。换句话说,要回答这个问题-多少就足够了？-必须考虑可以交付多少，需要交付多少。
