[11C]-metformin distribution in the liver and small intestine using dynamic PET in mice demonstrates tissue-specific transporter dependency

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DOI

Metformin is the most commonly prescribed oral anti-diabetic drug with well-documented beneficial preventive effects on diabetic complications. Despite being in clinical use for almost 60 years, the underlying mechanisms for metformin action remain elusive. Organic Cation Transporters (OCT) including Multidrug and Toxin Extrusion proteins (MATE) are essential for transport of metformin across membranes, but tissue-specific activity of these transporters in vivo is incompletely understood. Here, we use dynamic PET with C11-labelled metformin ([11C]-metformin) in mice to investigate the role of OCT and MATE in a well-established target tissue, the liver, and a putative target of metformin, the small intestine. Ablation of OCT1/2 significantly reduced the distribution of metformin in liver and small intestine. In contrast, inhibition of MATE1 with pyrimethamine caused accumulation of metformin in the liver but did not affect distribution in the small intestine. The demonstration of OCT-mediated transport into the small intestine provides evidence of direct effects of metformin in this tissue. OCT and MATE have important but separate roles in uptake and elimination of metformin in the liver, but this is not due to changes in biliary secretion. [11C]-metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies.

Original languageEnglish
JournalDiabetes
Pages (from-to)1724-1730
ISSN0012-1797
DOIs
Publication statusPublished - Jun 2016

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