PT  - JOURNAL ARTICLE
AU  - Choo, Edna F.
AU  - Leake, Brenda
AU  - Wandel, Christoph
AU  - Imamura, Hitoshi
AU  - Wood, Alastair J. J.
AU  - Wilkinson, Grant R.
AU  - Kim, Richard B.
TI  - Pharmacological Inhibition of P-glycoprotein Transport Enhances the Distribution of HIV-1 Protease Inhibitors into Brain and Testes
DP  - 2000 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 655--660
VI  - 28
IP  - 6
4099  - http://dmd.aspetjournals.org/content/28/6/655.short
4100  - http://dmd.aspetjournals.org/content/28/6/655.full
SO  - Drug Metab Dispos2000 Jun 01; 28
AB  - 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 [14C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with 14C-labeled amprenavir, indinavir, and saquinavir. Because [14C]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. The American Society for Pharmacology and Experimental Therapeutics