Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

• DOI: 10.1021/acs.molpharmaceut.5b00501
• Publication Date: 2015-11-03T18:18:33Z
• Authors: Xiaomin Liang; Huan-Chieh Chien; Sook Wah Yee; Marilyn M. Giacomini; Eugene C. Chen; Meiling Piao; Jia Hao; Jolyn Twelves; Eve-Irene Lepist; Adrian S. Ray; Kathleen M. Giaco...
• Keywords: 0301 basic medicine; 610; Small; Macromolecular and Materials Chemistry; Cell Line; Substrate Specificity; Mice; 03 medical and health sciences; Intestine, Small; Animals; Humans; Drug Interactions; Pharmacology & Pharmacy; Thiamine; Nutrition; Biomedical and Clinical Sciences; Membrane Transport Proteins; Biological Transport; Pharmacology and Pharmaceutical Sciences; THTR-2; Metformin; Intestine; drug and vitamin interaction; 3. Good health; Pharmacology and pharmaceutical sciences; HEK293 Cells; Intestinal Absorption; 5.1 Pharmaceuticals; SLC19A3; Digestive Diseases; metformin

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.