title: Emtricitabine: Inhibitor and substrate of multidrug resistance associated protein.
abstract: Efflux proteins have been shown to greatly affect the uptake of antiretroviral drugs by cells and to prevent their access to the HIV-1 replication site. The active efflux of these drugs might produce subtherapeutic drug levels and favor resistant viral strains and the emergence of sanctuary sites. This study has been performed to investigate whether emtricitabine (FTC) is a substrate and/or inhibitor of MRP1 in human peripheral blood mononuclear cells (PBMCs, HIV-1 target site). Moreover, we have reported the impact of FTC combined with protease inhibitors (PIs) (ritonavir, atazanavir, lopinavir) on Pgp and MRP1 expression and function, and on PI accumulation. Following a 72-h incubation with antiretroviral regimen, Pgp and MRP1 expression and function were assessed on lymphocytes; and intracellular drug concentrations were measured by LC-MS/MS. FTC concentrations were determined following incubation with or without specific efflux proteins inhibitors. FTC inhibitor properties were measured using 2 different MRP substrates. Quantitative real-time PCR showed that PBMCs express high levels of both Pgp and MRP1 mRNA copy number whereas MRP2 and MRP3 were not detectable. Our findings indicate a decrease in MRP1 function after exposure to FTC. MK571 (specific MRP inhibitor) significantly increases FTC accumulation in PBMCs. FTC increases intracellular calcein and [(3)H]-vincristine accumulation. Emtricitabine has both inhibitor and substrate characteristics with MRP1 in PBMCs in vitro, and does not interact with PI accumulation.
authors.affiliation: CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Gif sur Yvette Cedex, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bousquet
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
authors.forename: Nathalie
authors.initials: N
authors.lastname: Didier
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Aloïse
authors.initials: A
authors.lastname: Mabondzo
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents / Q000494:pharmacology*; D002853:Chromatography, Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068679:Emtricitabine; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014750:Vincristine / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D000998:Antiviral Agents; D003841:Deoxycytidine; D000068679:Emtricitabine; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D014750:Vincristine; C007740:fluorexon; C421109:multidrug resistance-associated protein 1