Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor
Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor
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DOI：
10.1023/a:1018941328702
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发表时间：
1999-08-01
影响因子：
3.7
通讯作者：
Woolley, JL
中科院分区：
文献类型：
--
作者：
Polli, JW;Jarrett, JL;Woolley, JL
目的。目的：探讨P-糖蛋白(Pgp)对HIV蛋白抑制剂氨丙那韦(141W94)中枢神经系统渗透的影响，并验证与另一种HIV PI(利托那韦)合用可增强Amprenavir体内脑渗透作用的假说。用Caco-2细胞体外和体内放射自显影(WBA)研究Pgp介导的外排。采用mdr1a/1b双基因敲除小鼠、给予Pgp抑制剂GF120918产生的化学性Pgp基因敲除小鼠以及利托那韦处理的小鼠进行WBA研究，观察Pgp对氨丙那韦中枢神经系统渗透的影响。Amprenavir、Indinavir、ritonavir和saquiavir的跨Caco-2单层的传输速率是从根尖方向到根尖方向的2-23倍。与GF120918孵育后，这种差异被否定，表明外排是由Pgp介导的。WBA研究表明，GF120918和mdr1a/1b双基因敲除小鼠的脑组织和脑脊液中氨丙那韦浓度分别增加了13倍和27倍，增加了3.3倍。相反，利托那韦的预处理不会改变氨丙那韦的中枢暴露。这些结果提供了证据，证明Amprenavir和其他HIV PI是Pgp底物，联合使用特定的Pgp抑制剂将增强Amprenavir在体内的中枢神经系统渗透。这些结果将对艾滋病痴呆的治疗产生重要的影响。
Purpose. To determine the role of P-glycoprotein (Pgp) on the CNS penetration of the HIV protease inhibitor (PI) amprenavir (141W94) and to test the hypothesis that co-administration of a second HIV PI (ritonavir) could enhance amprenavir's brain penetration in vivo.Methods. Pgp-mediated efflux was investigated in vitro with Caco-2 cells and in vivo by whole-body autoradiography (WBA). "Genetic" mdr1a/1b double knockout mice, "chemical" Pgp knockout mice generated by administration of the Pgp inhibitor GF120918, and mice pretreated with ritonavir were used in WBA studies to investigate the effects of Pgp modulation on the CNS penetration of amprenavir.Results. Amprenavir, indinavir, ritonavir, and saquinavir had 2-to 23-fold higher transport rates from the basolateral to apical direction than from the apical to basolateral direction across Caco-2 monolayers. Incubation with GF120918 negated this difference, suggesting that the efflux was Pgp-mediated. WBA studies demonstrated a 13- and 27-fold increase in the brain and a 3.3-fold increase in the CSF concentrations of amprenavir in mice pretreated with GF120918 and in mdr1a/1b double knockout mice. In contrast, pretreatment with ritonavir did not alter the CNS exposure of amprenavir.Conclusions. These results provide evidence that amprenavir and other HIV PIs are Pgp substrates and that co-administration of a specific Pgp inhibitor will enhance amprenavir's CNS penetration in vivo. These results will have an important therapeutic impact in the treatment of AIDS dementia.