Bcrp1的影响(Abcg2)体内的药物动力学和大脑渗透甲磺酸伊马替尼(格列卫):对乳腺癌抗蛋白质和22抑制剂的使用,使伊马替尼的病人的大脑渗透。
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Breedveld P, Pluim D, Cipriani G, Wielinga P范Tellingen O, Schinkel啊,Schellens JH
Bcrp1的影响(Abcg2)体内的药物动力学和大脑渗透甲磺酸伊马替尼(格列卫):对乳腺癌抗蛋白质和22抑制剂的使用,使伊马替尼的病人的大脑渗透。
癌症研究》2005年4月1日,65 (7):2577 - 82。
- PubMed ID
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15805252 (在PubMed]
- 文摘
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甲磺酸伊马替尼(格列卫信号传导抑制剂571)是一个强大的和有选择性的酪氨酸激酶抑制剂,这是证明有效地抑制血小板源生长因素胶质母细胞瘤细胞生长功能型。然而,在病人,普及率有限的伊马替尼进入大脑已被报道。伊马替尼是运输体外和体内22 (P-gp;ABCB1),从而限制了其分布到老鼠的大脑。以前,伊马替尼被证明强有力地抑制人类乳腺癌耐药蛋白(BCRP;ABCG2)。在这里,我们表明,伊马替尼是有效的运输通过鼠标Bcrp1转染Madin-Darby犬肾脏应变II (MDCKII)层。此外,我们表明,静脉输液伊马替尼的间隙显著减少1.6倍Bcrp1基因敲除小鼠与野生型小鼠相比。在t = 2小时,大脑渗透Bcrp1输液伊马替尼明显增加2.5倍的基因敲除小鼠与控制老鼠。我们测试的假设P-gp BCRP抑制剂,如elacridar和pantoprazole,改善大脑的渗透伊马替尼。 Firstly, we showed in vitro that pantoprazole and elacridar inhibit the Bcrp1-mediated transport of imatinib in MDCKII-Bcrp1 cells. Secondly, we showed that co-administration of pantoprazole or elacridar significantly reduced the clearance of i.v. imatinib in wild-type mice by respectively 1.7-fold and 1.5-fold. Finally, in wild-type mice treated with pantoprazole or elacridar, the brain penetration of i.v. imatinib significantly increased 1.8-fold and 4.2-fold, respectively. Moreover, the brain penetration of p.o. imatinib increased 5.2-fold when pantoprazole was co-administered in wild-type mice. Our results suggest that co-administration of BCRP and P-gp inhibitors may improve delivery of imatinib to malignant gliomas.