title: Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).
abstract: The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.
authors.forename: Huan-Chieh
authors.initials: HC
authors.lastname: Chien
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Giacomini
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Chen
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.|Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University , Beijing 100084, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Piao
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Jolyn
authors.initials: J
authors.lastname: Twelves
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Eve-Irene
authors.initials: EI
authors.lastname: Lepist
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc. , Foster City, California 94404, United States.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000032:analysis*; D008687:Metformin / Q000378:metabolism*; D051379:Mice; D013379:Substrate Specificity / Q000502:physiology; D013831:Thiamine / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human; D008687:Metformin; D013831:Thiamine
keywords: SLC19A3; THTR-2; drug and vitamin interaction; metformin