Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes

HIV protease inhibitors have proven remarkably effective in treating HIV-1 infection. However, some tissues such as the brain and testes (sanctuary si tes) 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 n ovel and potent P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) inc reased brain and testes concentration of [C-14]nelfinavir, up to 37- and 4- fold, respectively, in a dose-dependent fashion. Similar effects in brain l evels were also observed with C-14-labeled amprenavir, indinavir, and saqui navir. Because [C-14]nelfinavir plasma drug levels were only modestly incre ased 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 pen etration. Less potent P-glycoprotein inhibitors like valspodar (PSC-833), c yclosporin A, and ketoconazole, as well as quinidine and verapamil, had mod est or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectivel y, these findings provide "proof-of-concept" for increasing HIV protease in hibitor distribution into pharmacologic sanctuary sites by targeted inhibit ion of P-glycoprotein using selective and potent agents and suggest a new t herapeutic strategy to reduce HIV-1 viral replication.