Insight into the cooperation of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier: a case study examining sorafenib efflux clearance.
Insight into the cooperation of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier: a case study examining sorafenib efflux clearance.
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DOI：
10.1021/mp200465c
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发表时间：
2012-03-05
影响因子：
4.9
通讯作者：
Elmquist WF
中科院分区：
文献类型：
--
作者：
Agarwal S;Elmquist WF
atp结合盒转运蛋白p糖蛋白和乳腺癌耐药蛋白已被证明是限制药物通过血脑屏障转运到大脑的关键决定因素。一些治疗药物已被证明是这两种转运蛋白的底物，因此它们在大脑中的分布有限。最近，研究表明，这两种药物转运体在血脑屏障上相互合作，只有当两者都不存在时，双底物的脑渗透才会显著增加，例如在Mdr1a/1b-/- bcrp1 -/-小鼠中。本研究利用索拉非尼的脑渗透来研究这些发现，并试图用基于亲和力和容量依赖载体介导转运的简单理论来解释这种合作的机制基础。脑外排指数法结合脑器官型切片，确定P-gp和BCRP对索拉非尼脑外总清除率的净贡献，并表明其在血脑屏障的外排主要由BCRP介导。脑外索拉非尼清除率在Bcrp1-/-小鼠中下降2倍，在Mdr1a/1b-/-Bcrp1-/-小鼠中下降2.5倍。与野生型相比，P-gp缺失时脑清除率无显著变化。我们还研究了基因敲除动物中P-gp和BCRP的表达，发现与野生型小鼠相比，转运蛋白缺陷小鼠的P-gp和BCRP均无差异。总之，本研究通过分析索拉非尼的外排清除，并将其与决定清除的“机制”（即亲和力和容量）联系起来，解释了P-gp和BCRP的合作。
The ATP-binding cassette transporters p-glycoprotein and breast cancer resistance protein have been shown to be critical determinants limiting drug transport across the BBB into the brain. Several therapeutic agents have been shown to be substrates for these two transporters, and as a result they have limited distribution to the brain. Recently, it has been shown that these two drug transporters cooperate at the BBB and brain penetration of dual substrates increase significantly only when both are absent, e.g., in the Mdr1a/1b-/-Bcrp1-/- mice. The present study uses the brain penetration of sorafenib to investigate these findings and attempts to explain the mechanistic basis of this cooperation with a simple theory based on affinity and capacity dependent carrier-mediated transport. The brain efflux index method, combined with the organotypic brain slices, were used to determine the net contribution of P-gp and BCRP to the total clearance of sorafenib out of the brain and show that its efflux at the BBB is mediated primarily by BCRP. Sorafenib clearance out of the brain decreased 2-fold in the Bcrp1-/- mice and 2.5-fold in the Mdr1a/1b-/-Bcrp1-/- mice. Clearance out of brain when P-gp was absent did not change significantly compared to wild-type. We also investigated the expression of P-gp and BCRP in the genetic knockout animals and saw no differences in either P-gp or BCRP in the transporter deficient mice compared to the wild-type mice. In conclusion, this study explains the cooperation of P-gp and BCRP by analysis of the efflux clearance of sorafenib and correlating it to the ‘mechanisms’ that determine the clearance, i.e., affinity and capacity.
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