The Drug Transporter P-glycoprotein Limits Oral Absorption and Brain Entry of HIV-1 Protease Inhibitors.
Kim, Richard B.; Fromm, Martin F.; Wandel, Christoph; Leake, Brenda; Wood, Alastair J.J.; Roden, Dan M.; Wilkinson, Grant R.
[Miscellaneous Article] Journal of Clinical Investigation. 101(2):289-294, January 15, 1998.

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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. (J. Clin. Invest. 1998. 101:289-294.)

Copyright (C) 1998 The American Society for Clinical Investigation, Inc.