title: [11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency.
abstract: Metformin is the most commonly prescribed oral antidiabetic 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 positron emission tomography with [(11)C]-labeled metformin ([(11)C]-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 and OCT2 significantly reduced the distribution of metformin in the 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. [(11)C]-Metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies.
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Elias I
authors.initials: EI
authors.lastname: Sundelin
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Gormsen
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ole L
authors.initials: OL
authors.lastname: Munk
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark niels.jessen@clin.au.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
mesh_terms: D000818:Animals; D001692:Biological Transport; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008687:Metformin / Q000493:pharmacokinetics*; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D008687:Metformin