Effect of bovine serum albumin on drug permeability estimation across Caco-2 monolayers
Effect of bovine serum albumin on drug permeability estimation across Caco-2 monolayers
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DOI：
10.1016/s0939-6411(02)00089-9
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发表时间：
2002-11-01
影响因子：
4.9
通讯作者：
Kou, JH
中科院分区：
文献类型：
--
作者：
Saha, P;Kou, JH
本研究的目的是探索更准确地评估水溶性差的新化学实体（NCE）的Caco-2渗透性的方法，以确定具有更高置信度的生物药剂学分类系统（BCS）渗透性类别。在接收室中不存在或存在不同百分比的牛血清白蛋白（BSA）的情况下，研究了参比化合物和NCE（Sch-Y，Sch 56592）在Caco-2单层中的转运。在受体室中加入0.5- 4%BSA导致Sch-Y P-app增加4-5倍，而Sch 56592 P-app没有受到显著影响。在参比溶质中，仅地尔硫卓（log PC = 2.7，血浆蛋白结合率= 78%）的P-app比值（+BSA/cR）显著（1.3倍），但此类药物的人体口服吸收预测不受受体中存在BSA的影响。总之，转运研究期间在接收室中使用4% BSA可显著影响高度亲脂性NCE的估计Caco-2 P-app和BCS渗透性排名，如Sch-Y的情况，log PC为4.0。对于Sch-Y，这可能是由于改善了水槽条件和/或减少了塑料威尔斯孔的非特异性药物吸附。相比之下，基于估计的Caco-2 P-app值的Sch 56592渗透性分类（log PC = 2.4）不受存在受体BSA的影响。(C)2002 Elsevier Science B. V.保留所有权利。
The purpose of this study was to explore approaches to more accurately assess Caco-2 permeability of poorly water-soluble new chemical entities (NCEs) in an effort to determine their biopharmaceutics classification system (BCS) permeability class with a higher level of confidence. The transport of reference compounds and NCEs (Sch-Y, Sch 56592) was studied across Caco-2 monolayers in the absence or presence of varying percentage of bovine serum albumin (BSA) in the receiver chamber. The inclusion of 0.5-4% BSA in the receiver chamber caused a 4-5-fold increase in Sch-Y P-app, while Sch 56592 P-app was not significantly influenced. Amongst reference solutes, the P-app ratio (+BSA/ctrl) was significant (1.3-fold) only for diltiazem (log PC = 2.7, plasma protein binding = 78%), but the prediction of human oral absorption for such,drugs was not affected by the presence of BSA in receiver. In summary, the use of 4% BSA in the receiver chamber during transport studies can dramatically affect the estimated Caco-2 P-app and BCS permeability ranking of highly lipophilic NCEs, as in the case of Sch-Y with a log PC of 4.0. For Sch-Y, this is presumably due to improved sink conditions and/or a reduction in non-specific drug adsorption to plastic wells. In contrast, the permeability classification of Sch 56592 (log PC = 2.4) based on estimated Caco-2 P-app values is not affected by the presence of receiver BSA. (C) 2002 Elsevier Science B.V. All rights reserved.