The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors
The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors
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DOI：
10.1172/jci1269
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发表时间：
1998-01-15
影响因子：
15.9
通讯作者：
Wilkinson, GR
中科院分区：
文献类型：
--
作者：
Kim, RB;Fromm, MF;Wilkinson, GR
目前可用的HIV-1蛋白水解酶抑制剂是治疗HIV-1感染的有效药物。然而，有限的口服吸收和可变的组织分布，这两者在很大程度上都无法解释，这使得它们的使用变得复杂。我们验证了P-糖蛋白是这些药物的重要转运体的假设。我们利用表达P-糖蛋白的模型细胞株L-mdr1和Caco-2细胞体外研究了吲地那韦、奈非那韦和沙奎那韦的载体转运特性，并通过静脉和口服给药研究了这些药物对mdr1a基因突变小鼠的体内转运特性。这三个化合物都是通过P-糖蛋白在体外转运的。口服给药后，mdr1a(-/-)小鼠的血浆浓度升高2-5倍，静脉给药时，脑内浓度升高7-36倍。这些数据表明，P-糖蛋白限制了这些药物的口服生物利用度和脑内渗透。这增加了通过靶向药物抑制P-糖蛋白转运活性来获得更高的HIV-1蛋白酶抑制剂浓度的可能性。
Currently available HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution, both of which are largely unexplained, complicate their use. We tested the hypothesis that P-glycoprotein is an important transporter for these agents. We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene. All three compounds were found to be transported by P-glycoprotein in vitro. After oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous administration, brain concentrations were elevated 7-36-fold. These data demonstrate that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. This raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity.