title: The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.
abstract: Currently available HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution, both of which are largely unexplained, complicate their use. We tested the hypothesis that P-glycoprotein is an important transporter for these agents. We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene. All three compounds were found to be transported by P-glycoprotein in vitro. After oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous administration, brain concentrations were elevated 7-36-fold. These data demonstrate that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. This raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
authors.forename: M F
authors.initials: MF
authors.lastname: Fromm
authors.forename: C
authors.initials: C
authors.lastname: Wandel
authors.forename: B
authors.initials: B
authors.lastname: Leake
authors.forename: A J
authors.initials: AJ
authors.lastname: Wood
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
authors.forename: G R
authors.initials: GR
authors.lastname: Wilkinson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D018938:Caco-2 Cells; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D019888:Nelfinavir / Q000493:pharmacokinetics; D019258:Saquinavir / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease; D019888:Nelfinavir; D019258:Saquinavir