title: Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [(11)C]Metformin in Mouse.
abstract: OBJECTIVE
  To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using (11)C-labeled metformin ([(11)C]metformin) by positron emission tomography (PET).
  
  
  METHODS
  PET was performed by intravenous bolus injection of [(11)C]metformin. Pyrimethamine at 0.5 and 5 mg/kg was intravenously administered to mice 30 min prior to the scan. Integration plot analysis was conducted for calculating liver (CLuptake,liver), kidney (CLuptake,kidney) tissue uptake, intrinsic biliary (CLint,bile) and urinary (CLint,urine) excretion clearances of [(11)C]metformin.
  
  
  RESULTS
  Visualization by PET showed that pyrimethamine increased concentrations of [(11)C]metformin in the liver and kidneys, and decreased the concentrations in the urinary bladder without changing the blood profiles. Pyrimethamine had no effect on the CLuptake,liver and CLuptake,kidney, which were similar to the blood-flow rate. CLint,bile with regard to the liver concentration was unable to be determined, but administration of 0.5 and 5 mg/kg of pyrimethamine increased the liver-to-blood ratio to 1.6 and 2.3-fold, respectively, indicating that pyrimethamine inhibited the efflux of [(11)C]metformin from the liver. CLint,urine with regard to the corticomedullary region concentrations was decreased 37 and 68% of the control by administration of 0.5 and 5 mg/kg of pyrimethamine, respectively (P < 0.05).
  
  
  CONCLUSIONS
  Tissue concentration based investigations using [(11)C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.
authors.affiliation: RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Shingaki
authors.forename: W Ewan
authors.initials: WE
authors.lastname: Hume
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Takashima
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Katayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Emi
authors.initials: E
authors.lastname: Hayashinaka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Yilong
authors.initials: Y
authors.lastname: Cui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007668:Kidney / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011739:Pyrimethamine / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D007004:Hypoglycemic Agents; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D019275:Radiopharmaceuticals; D008687:Metformin; D011739:Pyrimethamine