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Research ArticleArticle

Pharmacokinetic and Pharmacodynamic Modeling of the Effect of an Sodium-Glucose Cotransporter Inhibitor, Phlorizin, on Renal Glucose Transport in Rats

Koji Yamaguchi, Motohiro Kato, Masayuki Suzuki, Kimie Asanuma, Yoshinori Aso, Sachiya Ikeda and Masaki Ishigai
Drug Metabolism and Disposition October 2011, 39 (10) 1801-1807; DOI: https://doi.org/10.1124/dmd.111.040048
Koji Yamaguchi
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Motohiro Kato
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Masayuki Suzuki
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Kimie Asanuma
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Yoshinori Aso
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Sachiya Ikeda
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Masaki Ishigai
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Abstract

A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium-glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy. First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2. This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption. The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance. The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption. The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2, which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model. The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.040048.

  • ABBREVIATIONS:

    SGLT
    sodium-glucose cotransporter
    PK-PD
    pharmacokinetic and pharmacodynamic
    GFR
    glomerular filtration rate
    BBMV
    brush-border membrane vesicles
    Km,SGLT1
    Michaelis-Menten constant of SGLT1 for glucose
    Km,SGLT2
    Michaelis-Menten constant of SGLT2 for glucose
    Vmax,SGLT1
    maximal transport capacity of SGLT1 for glucose
    Vmax,SGLT2
    maximal transport capacity of SGLT2 for glucose
    Ki,SGLT1
    inhibition constant for SGLT1
    Ki,SGLT2
    inhibition constant for SGLT2
    GE
    glucose excretion rate
    GF
    glucose filtration rate
    GR
    glucose reabsorption rate
    CLR,Glc
    renal glucose clearance
    HPLC
    high-performance liquid chromatography
    T-1095
    3-(benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone 2′-O-(6-O-methoxycarbonyl-β-d-glucopyranoside)
    AUC
    area under the curve.

  • Received April 11, 2011.
  • Accepted June 28, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

PK-PD MODEL FOR PHLORIZIN-EFFECT ON RENAL GLUCOSE TRANSPORT

Koji Yamaguchi, Motohiro Kato, Masayuki Suzuki, Kimie Asanuma, Yoshinori Aso, Sachiya Ikeda and Masaki Ishigai
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1801-1807; DOI: https://doi.org/10.1124/dmd.111.040048

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Research ArticleArticle

PK-PD MODEL FOR PHLORIZIN-EFFECT ON RENAL GLUCOSE TRANSPORT

Koji Yamaguchi, Motohiro Kato, Masayuki Suzuki, Kimie Asanuma, Yoshinori Aso, Sachiya Ikeda and Masaki Ishigai
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1801-1807; DOI: https://doi.org/10.1124/dmd.111.040048
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