title: Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein.
abstract: Saquinavir, a peptidomimetic HIV protease inhibitor, has been shown to be effective in reducing patient viral load and reducing mortality. In this report we investigated whether saquinavir is a substrate for the multidrug resistance transporter P-glycoprotein (P-gp), which may reduce the effective intracellular concentration of the drug. G185 cells, which highly express P-gp, are resistant to saquinavir-mediated cytotoxicity, and co-administration of cyclosporine reversed this resistance. Saquinavir and saquinavir mesylate inhibited basolateral to apical transport of the fluorescent dye rhodamine 123 in a polarized epithelial transport assay, a result that suggests competition of these drugs for the P-gp transporter. Finally, we measured specific, directional transport of saquinavir and saquinavir mesylate in an epithelial monolayer model. Transport in the basolateral to apical direction was 3-fold greater than apical to basolateral flux for both saquinavir and saquinavir mesylate and was blocked by co-incubation with the established P-gp reversal agents cyclosporine and verapamil. These data provide evidence that saquinavir is a substrate for the P-gp transporter and suggest that this protein may affect intracellular accumulation of the drug and contribute to its poor oral bioavailability.
authors.affiliation: Drug Transport Division, AvMax, Inc., Berkeley, California, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Kim
authors.forename: J M
authors.initials: JM
authors.lastname: Dintaman
authors.forename: D S
authors.initials: DS
authors.lastname: Waddell
authors.forename: J A
authors.initials: JA
authors.lastname: Silverman
mesh_terms: D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D051379:Mice; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D019258:Saquinavir / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012235:Rhodamines; D020112:Rhodamine 123; D016572:Cyclosporine; D019258:Saquinavir