Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec®) across the mouse blood-brain barrier
Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec®) across the mouse blood-brain barrier
复制标题
DOI：
10.1111/j.1471-4159.2007.04808.x
复制
发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Scherrmann, Jean-Michel
中科院分区：
文献类型：
--
作者：
Bihorel, Sebastien;Camenisch, Gian;Scherrmann, Jean-Michel
伊马替尼是一种蛋白酪氨酸激酶抑制剂，可以阻止胶质母细胞瘤细胞的生长。不幸的是，它的脑分布受到p糖蛋白（p-gp或多药耐药蛋白Mdr1a）和乳腺癌耐药蛋白（Bcrp1）的限制，这是在血脑屏障（BBB）表达的两个外排泵。我们使用原位脑灌注来研究伊马替尼在小鼠血脑屏障中的转运机制。野生型小鼠对伊马替尼的脑摄取受到饱和外排过程的限制。缬索达和佐苏魁达对p-gp的抑制增加了伊马替尼的摄取（2.5倍），Mdr1a/1b（-/-）小鼠中p-gp的缺乏也增加了（5.5倍）。将伊马替尼与p-gp/Bcrp1抑制剂埃拉西达灌注后，野生型小鼠（4.1倍）和Mdr1a/1b（-/-）小鼠（1.2倍）对伊马替尼的脑摄取增强。然而，当以非饱和浓度灌注时，野生型和Bcrp1（-/-）小鼠对伊马替尼的脑摄取是相似的。CGP74588（伊马替尼的一种活性代谢物）的脑摄取较低。埃拉西达（2倍）灌注可使其升高，而缬索达和佐苏魁达则无升高。Bcrp1（-/-）小鼠对CGP74588的摄取是野生型小鼠的1.5倍。这些数据表明，伊马替尼在小鼠血脑屏障的转运受到p-gp的限制，可能也受到Bcrp1的限制，CGP74588的转运受到Bcrp1的限制。
Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild-type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild-type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1.