Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar
Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar
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DOI：
10.1007/s11095-007-9278-4
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发表时间：
2007-09-01
影响因子：
3.7
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
选择性蛋白酪氨酸激酶抑制剂伊马替尼在临床前模型中抑制胶质瘤细胞的生长，但其较差的脑分布限制了其在患者中的疗效。P-糖蛋白（P-gp，啮齿动物Mdr 1a/1b或Abcb 1a/1b）和乳腺癌耐药蛋白（啮齿动物Bcrp 1或Abcg 2）被认为限制了伊马替尼向大脑的递送。本研究评估了这些转运蛋白的选择性抑制剂与伊马替尼联合给药对伊马替尼在小鼠体内的全身和大脑分布的影响。野生型、Mdr 1a/1b（-/-）和Bcrp 1（-/-）小鼠静脉给予伊马替尼，单独或与伐司泊达、佐舒喹达（P-gp抑制剂）或依克立达（P-gp和Bcrp 1抑制剂）联合给药。测定了[（14）C]伊马替尼及其放射性代谢物的血液和脑浓度。伐司泊达或佐舒喹达（> 3 mg/kg）阻断P-gp可增强野生型小鼠对伊马替尼的脑摄取（约4倍），但对其代谢物的摄取无影响。依克立达（> 3 mg/kg）阻断P-gp和Bcrp 1后，伊马替尼（9.3倍）及其代谢产物（2.8倍）的脑渗透率显著增加。相比之下，只有缺乏P-gp增强伊马替尼脑渗透（6.4倍）敲除小鼠。这些脑摄取的结果与我们组先前使用原位脑灌注获得的结果相当好地相关。伊马替尼及其代谢物渗透到脑中的能力较差，并且它们的渗透受到P-gp和（可能）Bcrp 1的限制。将伊马替尼与P-gp（和Bcrp 1）转运蛋白抑制剂（如依克立达）一起给药可能会改善伊马替尼向大脑的递送，使其对恶性胶质瘤更有效。
The selective protein tyrosine kinase inhibitor, imatinib, inhibits the growth of glioma cells in preclinical models, but its poor brain distribution limits its efficacy in patients. P-glycoprotein (P-gp, rodent Mdr1a/1b or Abcb1a/1b) and Breast cancer resistance protein (rodent Bcrp1 or Abcg2) were suggested to restrict the delivery of imatinib to the brain. This study evaluates the effect of administering selective inhibitors of these transporters together with imatinib on the systemic and cerebral disposition of imatinib in mice.Wild-type, Mdr1a/1b(-/-) and Bcrp1(-/-) mice were given imatinib intravenously, either alone, or with valspodar, zosuquidar (P-gp inhibitors), or elacridar (a P-gp and Bcrp1 inhibitor). The blood and brain concentrations of [(14) C]imatinib and its radioactive metabolites were determined.The blockade of P-gp by valspodar or zosuquidar (> 3 mg/kg) enhanced the brain uptake of imatinib (similar to 4-fold) in wild-type mice, but not that of its metabolites. Blockade of both P-gp and Bcrp1 by elacridar (> 3 mg/kg) produced significantly greater brain penetration of imatinib (9.3-fold) and its metabolites (2.8-fold). In contrast, only the lack of P-gp enhanced imatinib brain penetration (6.4-fold) in knockout mice. These results of brain uptake correlated reasonably well with those obtained previously by our group using in situ brain perfusion.Imatinib and its metabolites penetrate into the brain poorly and their penetration is limited by P-gp and (probably) Bcrp1. Administering imatinib together with P-gp (and Bcrp1) transporter inhibitors such as elacridar may improve the delivery of imatinib to the brain, making it potentially more effective against malignant gliomas.