Emtricitabine: Inhibitor and substrate of multidrug resistance associated protein

• Published in: European journal of pharmaceutical sciences Vol. 35; no. 4; pp. 247 - 256
• Main Authors: Bousquet, Laurence, Pruvost, Alain, Didier, Nathalie, Farinotti, Robert, Mabondzo, Aloïse
• Format: Journal Article
• Language: English
• Published: Kindlington Elsevier B.V 15.11.2008; Elsevier
• Subjects: ABC transporters; Animals; Antineoplastic Agents, Phytogenic - metabolism; Antiretroviral therapy; Antiretroviral Therapy, Highly Active; Antiviral Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family B - biosynthesis; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Chromatography, Liquid; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug efflux; Drug interactions; Emtricitabine; Flow Cytometry; Fluoresceins - metabolism; General pharmacology; Humans; Mass Spectrometry; Medical sciences; Multidrug resistance associated protein; Multidrug Resistance-Associated Proteins - biosynthesis; Multidrug Resistance-Associated Proteins - genetics; Neutrophils - drug effects; Neutrophils - metabolism; P-glycoprotein; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Vincristine - metabolism; P-glycoprotein; Multidrug resistance associated protein; ABC transporters; Drug efflux; Drug interactions; Antiretroviral therapy; Emtricitabine; Drug; Antiretroviral agent; Pharmaceutical technology; P Glycoprotein; Protein; Substrate; Treatment; Reverse transcriptase inhibitor; Multiple resistance; Nucleoside analog; Antiviral; Drug interaction; ABC transporter
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2008.06.017

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 [ 3H]-vincristine accumulation. Emtricitabine has both inhibitor and substrate characteristics with MRP1 in PBMCs in vitro, and does not interact with PI accumulation.