Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment
Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment
复制标题
DOI：
10.1158/1078-0432.ccr-08-2253
复制
发表时间：
2009-04-01
影响因子：
11.5
通讯作者：
Schinkel, Alfred H.
中科院分区：
文献类型：
--
作者：
Lagas, Jurjen S.;van Waterschoot, Robert A. B.;Schinkel, Alfred H.
目的：伊马替尼是一种BCR-ABL酪氨酸激酶抑制剂，是外排转运体p -糖蛋白（P-gp, ABCB1）和ABCG2（乳腺癌抵抗蛋白）的底物，其脑蓄积受到这两种转运体的限制。达沙替尼是一种SCR/BCR-ABL激酶抑制剂，与P-gp和ABCG2的体内相互作用尚未完全确定。实验设计：我们使用Abcb1a/1b（-/-）、Abcg2（-/-）和Abcb1a/1b；Abcg2（-/-）小鼠，建立P-gp和Abcg2在达沙替尼药代动力学和脑蓄积中的作用。结果：我们发现口服达沙替尼受P-gp限制。此外，Abcg2缺乏不影响给药后6小时脑内的相对蓄积，但P-gp缺乏导致口服给药后蓄积增加3.6倍，口服给药后蓄积增加4.8倍。Abcb1a / 1 b;Abcg2（-/-）小鼠的相对脑蓄积增加最为明显，口服后增加13.2倍，口服后增加22.7倍。此外，达沙替尼与双P-gp和ABCG2抑制剂埃拉西达共同给药野生型小鼠，导致达沙替尼脑积累与Abcb1a/1b相似；Abcg2(- / -)小鼠。结论：达沙替尼的脑蓄积主要受P-gp的限制，但Abcg2可以部分接管血脑屏障的保护功能。因此，当这两种转运蛋白缺失或受到抑制时，大脑对达沙替尼的摄取会大大增加。这些发现可能与中枢神经系统费城染色体阳性白血病患者的临床相关，因为P-gp和ABCG2抑制剂与达沙替尼共同给药可能会导致这些患者更好的治疗反应。
Purpose: Imatinib, a BCR-ABL tyrosine kinase inhibitor, is a substrate of the efflux transporters P-glycoprotein (P-gp, ABCB1) and ABCG2 (breast cancer resistance protein), and its brain accumulation is restricted by both transporters. For dasatinib, an inhibitor of SCR/BCR-ABL kinases, in vivo interactions with P-gp and ABCG2 are not fully established yet.Experimental Design: We used Abcb1a/1b(-/-), Abcg2(-/-), and Abcb1a/1b;Abcg2(-/-) mice to establish the roles of P-gp and ABCG2 in the pharmacokinetics and brain accumulation of dasatinib.Results: We found that oral uptake of dasatinib is limited by P-gp. Furthermore, relative brain accumulation, 6 hours after administration, was not affected by Abcg2 deficiency, but absence of P-gp resulted in a 3.6-fold increase after oral and 4.8-fold higher accumulation after i.p. administration. Abcb1a/1b;Abcg2(-/-) mice had the most pronounced increase in relative brain accumulation, which was 13.2-fold higher after oral and 22.7-fold increased after i.p. administration. Moreover, coadministration to wild-type mice of dasatinib with the dual P-gp and ABCG2 inhibitor elacridar resulted in a similar dasatinib brain accumulation as observed for Abcb1a/1b;Abcg2(-/-) mice.Conclusions: Brain accumulation of dasatinib is primarily restricted by P-gp, but Abcg2 can partly take over this protective function at the blood-brain barrier. Consequently, when both transporters are absent or inhibited, brain uptake of dasatinib is highly increased. These findings might be clinically relevant for patients with central nervous system Philadelphia chromosome-positive leukemia, as coadministration of an inhibitor of P-gp and ABCG2 with dasatinib might result in better therapeutic responses in these patients.