title: Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine.
abstract: The antiviral lamivudine is cleared predominantly by the kidney with a relevant contribution of renal tubular secretion. It is not clear which drug transporters mediate lamivudine renal secretion. Our aim was to investigate lamivudine as substrate of the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins MATE1 and MATE2-K. Uptake experiments were performed in OCT2, MATE1, or MATE2-K single-transfected human embryonic kidney 293 (HEK) cells. Transcellular transport experiments were performed in OCT2 and/or MATE1 single- or double-transfected Madin-Darby canine kidney II (MDCK) cells grown on transwell filters. Lamivudine uptake was significantly increased in HEK-OCT2, HEK-MATE1, and HEK-MATE2-K cells compared to control cells. In transcellular experiments, OCT2 located in the basolateral membrane had no effect on transcellular lamivudine transport. MATE1 located in the apical membrane decreased intracellular concentrations and increased transcellular transport of lamivudine from the basal to the apical compartment. MATE1- or MATE2-K-mediated transport was increased by an oppositely directed pH gradient. Several simultaneously administered drugs inhibited OCT2- or MATE2-K-mediated lamivudine uptake. The strongest inhibitors were carvedilol for OCT2 and trimethoprim for MATE2-K (inhibition by 96.3 and 83.7% at 15 μM, respectively, p<0.001). Trimethoprim inhibited OCT2- and MATE2-K-mediated lamivudine uptake with IC₅₀ values of 13.2 and 0.66 μM, respectively. Transcellular lamivudine transport in OCT2-MATE1 double-transfected cells was inhibited by trimethoprim with an IC₅₀ value of 6.9 μM. Lamivudine is a substrate of renal drug transporters OCT2, MATE1, and MATE2-K. Concomitant administration of drugs that inhibit these transporters could decrease renal clearance of lamivudine.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany. fabian.mueller@pharmakologie.med.uni-erlangen.de
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Eva
authors.initials: E
authors.lastname: Hoier
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mandery
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016764:Cell Polarity; D004285:Dogs; D004347:Drug Interactions; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D019259:Lamivudine / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D014162:Transfection; D014295:Trimethoprim / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D019259:Lamivudine; D014295:Trimethoprim
keywords: Drug transporter; Lamivudine; MATE; OCT2; Trimethoprim