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Research ArticleDrug Discovery and Translational Medicine

In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach

Koji Yamaguchi, Motohiro Kato, Masayuki Suzuki, Hitoshi Hagita, Maiko Takada, Miho Ayabe, Yoshinori Aso, Masaki Ishigai and Sachiya Ikeda
Journal of Pharmacology and Experimental Therapeutics April 2013, 345 (1) 52-61; DOI: https://doi.org/10.1124/jpet.113.203125
Koji Yamaguchi
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Motohiro Kato
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Masayuki Suzuki
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Hitoshi Hagita
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Maiko Takada
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Miho Ayabe
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Yoshinori Aso
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Masaki Ishigai
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Sachiya Ikeda
Research Division, Chugai Pharmaceutical Co., Ltd., (K.Y., M.K., M.S., M.T., M.A., Y.A., M.I., S.I.), and Chugai Research Institute for Medical Science, Inc. (H.H.), Gotemba, Shizuoka, Japan
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Abstract

To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (Ki) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r = 0.985; P < 0.05), with in vivo Ki values for SGLT2 in the range of 0.3–3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model.

Footnotes

    • Received January 8, 2013.
    • Accepted February 4, 2013.
  • The authors of this work are employees of Chugai Pharmaceutical or Chugai Research Institute for Medical Science and have not received financial support from any other institution.

  • dx.doi.org/10.1124/jpet.113.203125.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 1
1 Apr 2013
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Research ArticleDrug Discovery and Translational Medicine

IVIVC for Inhibition Potency of SGLT Inhibitors

Koji Yamaguchi, Motohiro Kato, Masayuki Suzuki, Hitoshi Hagita, Maiko Takada, Miho Ayabe, Yoshinori Aso, Masaki Ishigai and Sachiya Ikeda
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 52-61; DOI: https://doi.org/10.1124/jpet.113.203125

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Research ArticleDrug Discovery and Translational Medicine

IVIVC for Inhibition Potency of SGLT Inhibitors

Koji Yamaguchi, Motohiro Kato, Masayuki Suzuki, Hitoshi Hagita, Maiko Takada, Miho Ayabe, Yoshinori Aso, Masaki Ishigai and Sachiya Ikeda
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 52-61; DOI: https://doi.org/10.1124/jpet.113.203125
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