| 15180339 |
Ronaldson PT, Lee G, Dallas S, Bendayan R: Involvement of P-glycoprotein in the transport of saquinavir and indinavir in rat brain microvessel endothelial and microglia cell lines. Pharm Res. 2004 May;21(5):811-8.
PURPOSE: Membrane-bound efflux transporters, such as P-glycoprotein (P-gp), may limit the brain entry and distribution of HIV-1 protease inhibitors and be in part responsible for HIV-1-associated dementia treatment failure. The purpose of this study was to characterize the transport properties of saquinavir and indinavir in a brain microvessel endothelial cell line and in microglia, the immune cells of the brain and primary HIV-1 cellular target. METHODS: Biochemical and transport studies were performed in an immortalized rat brain endothelial cell line (RBE4), a rat microglia cell line (MLS-9), and a P-gp overexpressing Chinese hamster ovary cell line (CHRC5). RESULTS: Western blot analysis using the P-gp monoclonal antibody C219 detected a single band at approximately 170 to 180 kDa (a size previously reported for P-gp) in all cell lines. Cellular accumulation of [14C] saquinavir and [3H] indinavir by RBE4, MLS-9, and CHRC5 monolayers was significantly enhanced in the presence of P-gp inhibitors, HIV-1 protease inhibitors, the ATPase inhibitor sodium azide, and the ATP depleting agent 2',4'-dinitrophenol respectively. [14C] Saquinavir and [3H] indinavir efflux from both cell systems was rapid and significantly reduced in the presence of PSC833. CONCLUSIONS: These results provide evidence for P-gp mediated transport of saquinavir and indinavir in RBE4 and MLS-9 and suggest that this transporter can restrict, at least in part, the permeation of HIV-1 protease inhibitors at both the brain barrier site and in brain parenchyma. |
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