Choo E F, Leake B, Wandel C, Imamura H, Wood A J, Wilkinson G R, Kim R B
Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Drug Metab Dispos. 2000 Jun;28(6):655-60.
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.
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，一些组织如大脑和睾丸（庇护所部位）可能因位于毛细血管内皮的膜外排转运蛋白P-糖蛋白限制药物进入而免受HIV蛋白酶抑制剂的暴露。给小鼠静脉注射新型强效P-糖蛋白抑制剂LY-335979（1-50mg/kg），以剂量依赖方式使[(14)C]奈非那韦在大脑和睾丸中的浓度分别增加高达37倍和4倍。用(14)C标记的安普那韦、茚地那韦和沙奎那韦在大脑水平也观察到类似效果。由于LY-335979仅适度增加[(14)C]奈非那韦的血浆药物水平，大脑/血浆和睾丸/血浆比值分别增加14至17倍和2至5倍是由于组织渗透增加所致。效力较弱的P-糖蛋白抑制剂如伐司朴达（PSC-833）、环孢素A和酮康唑，以及奎尼丁和维拉帕米，对大脑/血浆比值影响不大或几乎没有影响，但由于抑制CYP3A介导的代谢而增加了血浆奈非那韦浓度。总体而言，这些发现为通过使用选择性强效药物靶向抑制P-糖蛋白来增加HIV蛋白酶抑制剂在药理庇护所部位的分布提供了“概念验证”，并提出了一种减少HIV-1病毒复制的新治疗策略。
