title: The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice.
abstract: Insufficient concentrations of protease inhibitors such as nelfinavir may reduce the effectiveness of HIV dementia treatment. The efflux transporter mdr1 product P-glycoprotein (P-gp) has been demonstrated to play a role in limiting nelfinavir brain levels. The goal of this study was to compare the effect of GF120918 (10 mg/kg, IV), a P-gp inhibitor, on intravenous nelfinavir (10 mg/kg) in vivo disposition and tissue penetration in P-gp-competent mdr1a/1b (+/+) mice versus P-gp double knockout mdr1a/1b (-/-) mice. Intravenous administration with the P-gp inhibitor GF120918 to mdr1a/1b (+/+) mice increased nelfinavir concentrations over a range of 2.3- to 27-fold, whereas nelfinavir distribution in mdr1a/1b (-/-) mice was 2- to 16-fold higher than that in their wild counterparts. Nelfinavir levels after GF120918 coadministration were higher in the heart, liver, and kidneys than those detected with mdr1a/1b knockout mice. In contrast, mdr1a/1b knockout mice exhibited higher nelfinavir levels in the brain (16.1-fold vs. 8.9-fold increase) and spleen (4.1-fold vs. 2.3-fold increase) compared to pharmacological inhibition with GF120918 in wild mice. Most notably, GF120918 provided tissue-specific effects in mdr1a/1b knockout mice with enhanced (p < 0.05) drug accumulation in the brain ( approximately 21-fold) and heart (3.3-fold). Our results suggest mdr1a/1b-independant mechanisms may also contribute to nelfinavir tissue distribution in mice.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.
authors.forename: Noha N
authors.initials: NN
authors.lastname: Salama
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kelly
authors.forename: Tot
authors.initials: T
authors.lastname: Bui
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019888:Nelfinavir / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D017320:HIV Protease Inhibitors; D044005:Tetrahydroisoquinolines; D019888:Nelfinavir; C083501:Elacridar