The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors

被引:893
作者
Kim, RB
Fromm, MF
Wandel, C
Leake, B
Wood, AJJ
Roden, DM
Wilkinson, GR
机构
[1] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA
关键词
P-glycoprotein; HIV-1 protease inhibitors; AIDS; membrane transport; pharmacokinetics;
D O I
10.1172/JCI1269
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:289 / 294
页数:6
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