title: Interactions of pluronic block copolymers on P-gp efflux activity: experience with HIV-1 protease inhibitors.
abstract: The objective was to examine the influence of Pluronic block-copolymers on the interaction between the drug efflux transporter, P-glycoprotein and HIV-1 protease inhibitors (PIs). The ATPase assay determined the effect of various Pluronics on PI-stimulated P-gp ATPase activity. Cellular accumulation studies were conducted using MDCKII and LLC-PK1 cells transfected with human MDR1 to assess Pluronic modulation of PI efflux. Pluronic P85 inhibited both basal and nelfinavir-stimulated P-gp ATPase activity, while Pluronic F127 had no effect. In cell accumulation studies, Pluronic P85 restored the accumulation of nelfinavir in MDCKII-MDR1 cells while Pluronic F127 and F88 had no effect. Pluronic P85 increased saquinavir accumulation in wild-type and MDR1-transfected cells in both the MDCKII and LLC-PK1 cell models, suggesting inhibition of multiple transporters, including MRPs. In conclusion, this study provides evidence that a block-copolymer, Pluronic P85, effectively inhibits the interaction of P-gp with nelfinavir and saquinavir. These data indicate that effective inhibition of HIV-1 PI efflux by Pluronic P85 may influence the distribution of antiretroviral agents to sites protected by efflux mechanisms, such as the blood-brain barrier, and possibly increase the brain exposure of these drugs resulting in suppression of viral replication and reduction in the incidence of drug resistant mutants.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard St. SE, Room 9-125d, Weaver-Densford Hall, Minneapolis, Minnesota 55455, USA.
authors.forename: Naveed
authors.initials: N
authors.lastname: Shaik
authors.forename: Guoyu
authors.initials: G
authors.lastname: Pan
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D020442:Poloxamer / Q000494:pharmacology*; D013552:Swine
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D017320:HIV Protease Inhibitors; D020442:Poloxamer