Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [11C]Metformin in Mouse
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To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using 11C-labeled metformin ([11C]metformin) by positron emission tomography (PET).
PET was performed by intravenous bolus injection of [11C]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 [11C]metformin.
Visualization by PET showed that pyrimethamine increased concentrations of [11C]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 [11C]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).
Tissue concentration based investigations using [11C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.
Key WordsDrug-drug interactions (DDIs) Metformin Multidrug and toxin extrusion proteins (Mates) Organic cation transporters (Octs) Positron emission tomography (PET)
The area under the concentration-time curve
- CLint,bile or urine
The intrinsic bile or urinary excretion clearances
The renal clearance
The total body clearance
The uptake clearance in the liver or kidney
Human multidrug and toxin extrusion proteins
Mouse multidrug and toxin extrusion proteins
Human organic cation transporters
Mouse organic cation transporters
Positron emission tomography
Regions of interest
Extravascular space volume
Volumetric regions of interest
We thank Mr. Masahiro Kurahashi of Sumitomo Heavy Industry Accelerator Service Ltd. for operation of the cyclotron. This study was partly carried out as the Research Project for the “Establishment of Evolutional Drug Development with the Use of Microdose Clinical Trial” sponsored by the New Energy and Industrial Technology Development Organization. Part of this work was also supported by JSPS KAKENHI Grant number 24229002.
Conflict of Interest
The authors report no conflicts of interest.
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