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Pharmaceutical Research

, Volume 32, Issue 8, pp 2538–2547 | Cite as

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

  • Tomotaka Shingaki
  • W. Ewan Hume
  • Tadayuki Takashima
  • Yumiko Katayama
  • Takashi Okauchi
  • Emi Hayashinaka
  • Yasuhiro Wada
  • Yilong Cui
  • Hiroyuki Kusuhara
  • Yuichi Sugiyama
  • Yasuyoshi WatanabeEmail author
Research Paper
  • 485 Downloads

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.

Key Words

Drug-drug interactions (DDIs) Metformin Multidrug and toxin extrusion proteins (Mates) Organic cation transporters (Octs) Positron emission tomography (PET) 

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

Notes

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.

Supplementary material

11095_2015_1642_MOESM1_ESM.tif (69 kb)
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)
11095_2015_1642_Fig7_ESM.gif (24 kb)
(GIF 23 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tomotaka Shingaki
    • 1
  • W. Ewan Hume
    • 1
  • Tadayuki Takashima
    • 2
  • Yumiko Katayama
    • 1
  • Takashi Okauchi
    • 1
  • Emi Hayashinaka
    • 1
  • Yasuhiro Wada
    • 1
  • Yilong Cui
    • 1
  • Hiroyuki Kusuhara
    • 3
  • Yuichi Sugiyama
    • 4
  • Yasuyoshi Watanabe
    • 1
    Email author
  1. 1.RIKEN Center for Life Science Technologies6-7-3 Minatojima-minamimachiKobeJapan
  2. 2.RIKEN Center for Molecular Imaging SciencesWhere Reorganized to RIKEN Center for Life Science TechnologiesKobeJapan
  3. 3.Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  4. 4.Sugiyama Laboratory, RIKEN Innovation CenterYokohama Bio Industry CenterYokohamaJapan

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