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.

Keywords:

• Cimetidine
• combination antiretroviral therapy
• drug–drug interactions
• MDCK cells
• pharmacokinetics
• ritonavir

Acknowledgements

We thank Prof Martin F. Fromm (Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany) for providing us with the MDCK cell lines stably transfected with OCT1, OCT2 and/or MATE1 transporters.

Declaration of interest

The authors report no declarations of interest. This study was financially supported by the Grant Agency of the Charles University in Prague [GAUK 1148213/C/2013]; the Czech Science Foundation [GACR 303/13-31118P]; and SVV/2015/260-185. The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. F. M. is current employee of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.