Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.
Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.
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发表时间：
2000-06
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通讯作者：
E. Choo;B. Leake;C. Wandel;H. Imamura;A. J. Wood;G. Wilkinson;R. Kim
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作者：
E. Choo;B. Leake;C. Wandel;H. Imamura;A. J. Wood;G. Wilkinson;R. Kim
HIV蛋白酶抑制剂已被证明在治疗HIV-1感染方面非常有效。然而，由于药物进入受到位于毛细血管内皮中的膜外排转运蛋白P-糖蛋白的限制，一些组织如脑和睾丸（保护区）可能受到保护，免于暴露于HIV蛋白酶抑制剂。小鼠静脉注射新型强效P-糖蛋白抑制剂LY-335979（1-50 mg/kg）可使[（14）C]奈非那韦的脑和睾丸浓度分别增加37倍和4倍，呈剂量依赖性。在（14）C标记的安普那韦、茚地那韦和沙奎那韦中也观察到了类似的脑水平效应。由于LY-335979仅适度增加[（14）C]奈非那韦血浆药物水平，因此脑/血浆和睾丸/血浆比值分别增加14- 17倍和2- 5倍，这是由于组织渗透增加。效力较低的P-糖蛋白抑制剂，如伐司泊达（PSC-833）、环孢菌素A和酮康唑以及奎尼丁和维拉帕米，对脑/血浆比值有中度或很小的影响，但由于抑制CYP 3A介导的代谢而增加了奈非那韦的血浆浓度。总的来说，这些研究结果提供了“概念验证”增加HIV蛋白酶抑制剂分布到药理学避难所网站的靶向抑制P-糖蛋白使用选择性和有效的代理，并提出了一种新的治疗策略，以减少HIV-1病毒复制。
HIV protease inhibitors have proven remarkably effective in treating HIV-1 infection. However, some tissues such as the brain and testes (sanctuary sites) are possibly protected from exposure to HIV protease inhibitors due to drug entry being limited by the membrane efflux transporter P-glycoprotein, located in the capillary endothelium. Intravenous administration of the novel and potent P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) increased brain and testes concentration of [(14)C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with (14)C-labeled amprenavir, indinavir, and saquinavir. Because [(14)C]nelfinavir plasma drug levels were only modestly increased by LY-335979, the increase in brain/plasma and testes/plasma ratios of 14- to 17- and 2- to 5-fold, respectively, was due to increased tissue penetration. Less potent P-glycoprotein inhibitors like valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as quinidine and verapamil, had modest or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectively, these findings provide "proof-of-concept" for increasing HIV protease inhibitor distribution into pharmacologic sanctuary sites by targeted inhibition of P-glycoprotein using selective and potent agents and suggest a new therapeutic strategy to reduce HIV-1 viral replication.