european journal of pharmaceutical sciences 35 ( 2 0 0 8 ) 247–256 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/ejps Emtricitabine: Inhibitor and substrate of multidrug resistance associated protein Laurence Bousquet a,b , Alain Pruvost a , Nathalie Didier a , Robert Farinotti b , Aloïse Mabondzo a,∗ a CEA, iBiTec-S, Service de Pharmacologie et d’Immunoanalyse, Bâtiment 136, 91191 Gif sur Yvette Cedex, France b Pharmacie Clinique, EA 2706 Barrières et Passage des Médicaments, Université Paris Sud, XI, Faculté de Pharmacie, 92296 Châtenay-Malabry, France article info Article history: Received 30 November 2007 Received in revised form 15 May 2008 Accepted 30 June 2008 Published on line 18 July 2008 Keywords: ABC transporters Antiretroviral therapy Drug efflux Drug interactions Multidrug resistance associated protein P-glycoprotein 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 tar- get 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 mea- sured 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) sig- nificantly 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. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Currently available antiretroviral agents belong to four dif- ferent classes: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs, NtRTIs), non-nucleoside reverse transcrip- tase inhibitors (NNRTIs), protease inhibitors (PIs), and a new ∗ Corresponding author. Tel.: +33 1 69 08 13 21; fax: +33 1 69 08 59 07. E-mail address: Aloise.Mabondzo@cea.fr (A. Mabondzo). class of fusion inhibitors (FIs). The combined administration of at least 3 drugs from different drug classes as highly active antiretroviral therapy (HAART) has been shown to slow the progression of diseases, improve survival, and result in better virologic and immunologic responses (Chearskul et al., 2006). The effectiveness of HAART is challenged by viral resistance 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.06.017