title: In Vivo Imaging of Human 11C-Metformin in Peripheral Organs: Dosimetry, Biodistribution, and Kinetic Analyses.
abstract: Metformin is the most widely prescribed oral antiglycemic drug, with few adverse effects. However, surprisingly little is known about its human biodistribution and target tissue metabolism. In animal experiments, we have shown that metformin can be labeled by11C and that11C-metformin PET can be used to measure renal function. Here, we extend these preclinical findings by a first-in-human11C-metformin PET dosimetry, biodistribution, and tissue kinetics study.
  
  
  METHODS
  Nine subjects (3 women and 6 men) participated in 2 studies: in the first study, human radiation dosimetry and biodistribution of11C-metformin were estimated in 4 subjects (2 women and 2 men) by whole-body PET. In the second study,11C-metformin tissue kinetics were measured in response to both intravenous and oral radiotracer administration. A dynamic PET scan with a field of view covering target tissues of metformin (liver, kidneys, intestines, and skeletal muscle) was obtained for 90 (intravenous) and 120 (oral) min.
  
  
  RESULTS
  Radiation dosimetry was acceptable, with effective doses of 9.5 μSv/MBq (intravenous administration) and 18.1 μSv/MBq (oral administration). Whole-body PET revealed that11C-metformin was primarily taken up by the kidneys, urinary bladder, and liver but also to a lesser extent in salivary glands, skeletal muscle, and intestines. Reversible 2-tissue-compartment kinetics was observed in the liver, and volume of distribution was calculated to be 2.45 mL/mL (arterial input) or 2.66 mL/mL (portal and arterial input). In the kidneys, compartmental models did not adequately fit the experimental data, and volume of distribution was therefore estimated by a linear approach to be 6.83 mL/mL. Skeletal muscle and intestinal tissue kinetics were best described by 2-tissue-compartment kinetics and showed only discrete tracer uptake. Liver11C-metformin uptake was pronounced after oral administration of the tracer, with tissue-to-blood ratio double what was observed after intravenous administration. Only slow accumulation of11C-metformin was observed in muscle. There was no elimination of11C-metformin through the bile both during the intravenous and during the oral part of the study.
  
  
  CONCLUSIONS
  11C-metformin is suitable for imaging metformin uptake in target tissues and may prove a valuable tool to assess the impact of metformin treatment in patients with varying metformin transport capacity.
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark lars.christian.gormsen@clin.au.dk.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Gormsen
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Elias Immanuel
authors.initials: EI
authors.lastname: Sundelin
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jonas Brorson
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mikkel Holm
authors.initials: MH
authors.lastname: Vendelbo
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ole Lajord
authors.initials: OL
authors.lastname: Munk
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Mette Marie
authors.initials: MM
authors.lastname: Hougaard Christensen
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.|Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark; and.
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
mesh_terms: D000328:Adult; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics*; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D011874:Radiometry; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D002250:Carbon Radioisotopes; D008687:Metformin
keywords: 11C-metformin; PET/CT; biodistribution; metformin