Steen Jakobsen

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

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[11C]-metformin distribution in the liver and small intestine using dynamic PET in mice demonstrates tissue-specific transporter dependency. / Jensen, Jonas B; Sundelin, Elias I; Jakobsen, Steen; Gormsen, Lars C; Munk, Ole L; Frøkiær, Jørgen; Jessen, Niels.

In: Diabetes, 06.2016, p. 1724-1730.

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@article{09e6239459104b478c8c39d3bb7e7a62,
title = "[11C]-metformin distribution in the liver and small intestine using dynamic PET in mice demonstrates tissue-specific transporter dependency",
abstract = "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.",
author = "Jensen, {Jonas B} and Sundelin, {Elias I} and Steen Jakobsen and Gormsen, {Lars C} and Munk, {Ole L} and J{\o}rgen Fr{\o}ki{\ae}r and Niels Jessen",
note = "{\circledC} 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.",
year = "2016",
month = "6",
doi = "10.2337/db16-0032",
language = "English",
pages = "1724--1730",
journal = "Diabetes",
issn = "0012-1797",
publisher = "AMER DIABETES ASSOC",

}

RIS

TY - JOUR

T1 - [11C]-metformin distribution in the liver and small intestine using dynamic PET in mice demonstrates tissue-specific transporter dependency

AU - Jensen, Jonas B

AU - Sundelin, Elias I

AU - Jakobsen, Steen

AU - Gormsen, Lars C

AU - Munk, Ole L

AU - Frøkiær, Jørgen

AU - Jessen, Niels

N1 - © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PY - 2016/6

Y1 - 2016/6

N2 - 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.

AB - 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.

U2 - 10.2337/db16-0032

DO - 10.2337/db16-0032

M3 - Journal article

SP - 1724

EP - 1730

JO - Diabetes

JF - Diabetes

SN - 0012-1797

ER -