P-glycoprotein and breast cancer resistance protein: Two dominant transporters working together in limiting the brain penetration of topotecan
P-glycoprotein and breast cancer resistance protein: Two dominant transporters working together in limiting the brain penetration of topotecan
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DOI：
10.1158/1078-0432.ccr-07-1335
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发表时间：
2007-11-01
影响因子：
11.5
通讯作者：
van Tellingen, Olaf
中科院分区：
文献类型：
--
作者：
de Vries, Nienke A.;Zhao, Jin;van Tellingen, Olaf
目的：由于血脑屏障（BBB）的存在，脑是药理学的避难所。尽管P-糖蛋白（P-gp）在BBB中的作用已被充分确立，但也在BBB中表达的乳腺癌耐药蛋白（BCRP）的作用尚未确定。我们研究了拓扑替康对野生型（WT）、单一Mdr 1 a/B（-/-）和Bcrp 1（（-/-））的影响，和化合物Mdr 1a/B（（-/-））Bcrp 1（（-/-））敲除小鼠。通过高效液相色谱法测定血浆和组织中的药物水平。Mdr 1a/B（（-/-））和Bcrp 1（（-/-））小鼠脑中拓扑替康的血浆和组织浓度-时间曲线下面积（AUC）仅为WT小鼠的1.5倍，但在Mdr 1a/B（（-/-））Bcrp 1（（（-/-））小鼠中，两种转运蛋白均不存在，AUC增加了12倍。Mdr 1a/B（（-/-））、Bcrp 1（（-/-））和Mdr 1a/B（（-/-））Bcrp 1（（-/-））小鼠的血浆AUC分别高0.75、2.4和3.7倍，导致2.0倍01）、0.65倍（P，不显著）和3.2倍（P < 0.01），脑-血浆AUC比更高。使用Mrp 4（（-/-））小鼠的结果表明，该转运蛋白对拓扑替康的脑渗透没有影响。P-gp/BCRP抑制剂依克立达完全抑制P-gp介导的托泊替康转运，而依克立达抑制Bcrp 1介导的转运是minimal.Conclusions：我们的研究结果使用Mdr 1a/B（（-/-））Bcrp 1（（-/-））小鼠清楚地显示了Bcrp 1在BB B的效果，也显示了两种药物转运蛋白如何协同作用，以限制托泊替康的脑渗透。我们预计这一发现也适用于作为P-gp和BCRP底物的其他药物。因此，为了改善这些化合物的脑渗透以靶向患者的颅内恶性肿瘤，使用两种药物转运蛋白的有效抑制剂将是至关重要的。
Purpose: The brain is a pharmacologic sanctuary site, due to the presence of the blood-brain barrier (BBB). Whereas the effect of P-glycoprotein (P-gp) at the BBB is well established, the role of breast cancer resistance protein (BCRP) that is also expressed at the BBB is not.Experimental Design: We have studied the effect of BCRP by administering topotecan to wildtype (WT), single Mdr1a/b((-/-)) and Bcrp1((-/-))), and compound Mdr1a/b((-/-))Bcrp1((-/-)) knockout mice. Drug levels in plasma and tissues were determined by high-performance liquid chromatography.Results: The area under the plasma and tissue concentration-time curve (AUC) of topotecan in brains of Mdr1a/b((-/-)) and Bcrp1((-/-)) mice was only 1.5-fold higher compared with WT mice, but in Mdr1a/b((-/-)) Bcrp1((-/-)) mice, where both transporters are absent, the AUC increased by 12-fold. The AUC in plasma was similar to 0.75-, 2.4-, and 3.7-fold higher in Mdr1a/b((-/-)), Bcrp1((-/-)), and Mdr1a/b((-/-)) Bcrp1((-/-)) mice, respectively, resulting in 2.0-fold (P < 0.01), 0.65-fold (P, not significant), and 3.2-fold (P < 0.01), respectively, higher brain-to-plasma AUC ratios. Results using Mrp4((-/-)) mice showed that this transporter had no effect on the brain penetration of topotecan. The P-gp/BCRP inhibitor elacridar fully inhibited P-gp - mediated transport of topotecan, whereas inhibition of Bcrp1-mediated transport by elacridar was minimal.Conclusions: Our results using Mdr1a/b((-/-)) Bcrp1((-/-)) mice clearly show the effect of Bcrp1 at the BBB and also show how two drug transporters act in concert to limit the brain penetration of topotecan. We expect that this finding will also apply to other drugs that are substrates of both P-gp and BCRP. Consequently, to improve the brain penetration of such compounds for targeting intracranial malignancies in patients, it will be essential to use potent inhibitors of both drug transporters.