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Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [11C]Metformin in Mouse

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Abstract

Purpose

To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using 11C-labeled metformin ([11C]metformin) by positron emission tomography (PET).

Methods

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.

Results

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).

Conclusions

Tissue concentration based investigations using [11C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.

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Abbreviations

AUC:

The area under the concentration-time curve

CLint,bile or urine :

The intrinsic bile or urinary excretion clearances

CLrenal :

The renal clearance

CLtot :

The total body clearance

CLuptake,organ :

The uptake clearance in the liver or kidney

MATEs:

Human multidrug and toxin extrusion proteins

mMates:

Mouse multidrug and toxin extrusion proteins

OCTs:

Human organic cation transporters

mOcts:

Mouse organic cation transporters

PET:

Positron emission tomography

ROIs:

Regions of interest

VE :

Extravascular space volume

VOIs:

Volumetric regions of interest

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Tomotaka Shingaki, W. Ewan Hume, Yumiko Katayama, Takashi Okauchi, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui & Yasuyoshi Watanabe

  2. RIKEN Center for Molecular Imaging Sciences, Where Reorganized to RIKEN Center for Life Science Technologies, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Tadayuki Takashima

  3. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hiroyuki Kusuhara

  4. Sugiyama Laboratory, RIKEN Innovation Center, Yokohama Bio Industry Center, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan

    Yuichi Sugiyama

Authors
  1. Tomotaka Shingaki
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Corresponding author

Correspondence to Yasuyoshi Watanabe.

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Supplemental Fig. 1

Time-radioactivity curves in the right ventricle obtained from PET imaging data analysis and the radioactivity in blood sample determined by gamma-counter. Open symbols represent control mice (n = 3; circles) and mice treated with 0.5 and 5 mg/kg of pyrimethamine (n = 4; triangles, n = 3; squares) from PET imaging data analysis. Closed symbols represent control mice (n = 3; circles) and mice treated with 0.5 and 5 mg/kg of pyrimethamine (n = 3; triangles, n = 3; squares) from blood sample determined by gamma-counter. (TIFF 68 kb)

(GIF 23 kb)

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Shingaki, T., Hume, W.E., Takashima, T. et al. Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [11C]Metformin in Mouse. Pharm Res 32, 2538–2547 (2015). https://doi.org/10.1007/s11095-015-1642-1

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  • DOI: https://doi.org/10.1007/s11095-015-1642-1

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