title: Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.
abstract: 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.
authors.affiliation: Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: Choo
authors.forename: B
authors.initials: B
authors.lastname: Leake
authors.forename: C
authors.initials: C
authors.lastname: Wandel
authors.forename: H
authors.initials: H
authors.lastname: Imamura
authors.forename: A J
authors.initials: AJ
authors.lastname: Wood
authors.forename: G R
authors.initials: GR
authors.lastname: Wilkinson
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D011804:Quinolines / Q000494:pharmacology*; D013737:Testis / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D017320:HIV Protease Inhibitors; D011804:Quinolines; C095179:zosuquidar trihydrochloride