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Mol Pharm. 2015 Dec 7;12(12):4301-10. doi: 10.1021/acs.molpharmaceut.5b00501. Epub 2015 Nov 16.

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94158, United States.
2
Department of Drug Metabolism, Gilead Sciences, Inc. , Foster City, California 94404, United States.
3
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University , Beijing 100084, China.

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.

KEYWORDS:

SLC19A3; THTR-2; drug and vitamin interaction; metformin

PMID:
26528626
PMCID:
PMC4800991
DOI:
10.1021/acs.molpharmaceut.5b00501
[Indexed for MEDLINE]
Free PMC Article

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