Involvement of P-glycoprotein in the transport of saquinavir and indinavir in rat brain microvessel endothelial and microglia cell lines

Patrick T. Ronaldson, Gloria Lee, Shannon Dallas, Reina Bendayan

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)811-818
Number of pages8
JournalPharmaceutical Research
Volume21
Issue number5
DOIs
StatePublished - May 1 2004
Externally publishedYes

Keywords

  • Central nervous system
  • Drug transport
  • Indinavir
  • P-glycoprotein
  • Saquinavir

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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