title: Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters.
abstract: 1. Emtricitabine is a nucleoside reverse transcriptase inhibitor used in combination antiretroviral therapy of HIV (cART). Although active transport mechanisms are believed to mediate tubular secretion of the drug into urine, the responsible transporter and its potential to cause pharmacokinetic drug--drug interactions (DDI) has not been identified so far. The aim of this study was to investigate whether drug transporters P-gp (ABCB1), BCRP (ABCG2), MRP2 (ABCC2), OCT1 (SLC22A1), OCT2 (SLC22A2) or MATE1 (SLC47A1) can mediate active transcellular transfer of emtricitabine. 2. We employed transport assays in polarized monolayers of MDCK cells stably expressing P-gp, BCRP, MRP2, OCT1, OCT2 and/or MATE1. Among the transporters studied only MATE1 accelerated basal-to-apical transport of emtricitabine over a wide range of concentrations (6 nM to 1 mM). The transport was enhanced by an oppositely directed pH gradient and significantly reduced (p < 0.001) at low temperature in MDCK-MATE1, MDCK-OCT1/MATE1 and MDCK-OCT2/MATE1 cells. Co-administration of cimetidine or ritonavir decreased MATE1-mediated transport of emtricitabine by up to 42 and 39%, respectively (p < 0.01) and augmented intracellular accumulation of emtricitabine (p < 0.05). 3. We demonstrate emtricitabine as a substrate of MATE1 and suggest that MATE1 might cause DDI between emtricitabine and other co-administrated drugs including antiretrovirals.
authors.affiliation: a Department of Pharmacology and Toxicology , Faculty of Pharmacy, Charles University in Prague , Hradec Kralove , Czech Republic and.
authors.forename: Josef
authors.initials: J
authors.lastname: Reznicek
authors.affiliation: a Department of Pharmacology and Toxicology , Faculty of Pharmacy, Charles University in Prague , Hradec Kralove , Czech Republic and.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.affiliation: a Department of Pharmacology and Toxicology , Faculty of Pharmacy, Charles University in Prague , Hradec Kralove , Czech Republic and.
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.affiliation: b Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.affiliation: a Department of Pharmacology and Toxicology , Faculty of Pharmacy, Charles University in Prague , Hradec Kralove , Czech Republic and.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D004285:Dogs; D000068679:Emtricitabine / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027701:Organic Cation Transport Proteins; D018894:Reverse Transcriptase Inhibitors; D000068679:Emtricitabine
keywords: Cimetidine; MDCK cells; combination antiretroviral therapy; drug–drug interactions; pharmacokinetics; ritonavir