The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.

Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR
J Clin Invest. 1998 101 (2): 289-94

PMID: 9435299 · PMCID: PMC508566 · DOI:10.1172/JCI1269

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.

MeSH Terms (12)

Animals ATP Binding Cassette Transporter, Subfamily B, Member 1 Caco-2 Cells HIV Protease HIV Protease Inhibitors Humans Indinavir Intestinal Absorption Male Mice Nelfinavir Saquinavir

Connections (1)

This publication is referenced by other Labnodes entities: