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Research ArticleNeuropharmacology

Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

David L. Bourdet, Pamela R. Tsuruda, Glenmar P. Obedencio and Jacqueline A. M. Smith
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 137-145; DOI: https://doi.org/10.1124/jpet.111.188417
David L. Bourdet
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Pamela R. Tsuruda
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Glenmar P. Obedencio
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Jacqueline A. M. Smith
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Abstract

Translation of central nervous system occupancy and clinical effect from animal models to humans has remained elusive for many pharmacological targets. The current studies evaluate the ability of a rodent pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to translate ex vivo occupancy determined in rats to that observed after positron emission tomography (PET) imaging in humans for the dual serotonin transporter (SERT) and norepinephrine transporter (NET) inhibitor duloxetine. Ex vivo transporter occupancy in rat spinal cord was evaluated after single oral doses of 0.3 to 60 mg/kg. A novel methodology, based on the initial rates of association of transporter selective radioligands to tissue homogenates, was developed and validated for the assessment of ex vivo transporter occupancy. Duloxetine exhibited selectivity for occupancy of SERT over NET in rat spinal cord with ED50 values of 1 and 9 mg/kg, respectively. Corresponding EC50 values for the inhibition of SERT and NET based on unbound duloxetine spinal cord concentrations were 0.5 and 8 nM. An effect compartment PK/PD modeling approach was used to analyze the relationship between the time course of duloxetine plasma concentration and SERT and NET occupancy. Duloxetine inhibited SERT and NET in rat spinal cord with a plasma EC50 of 2.95 and 59.0 ng/ml, respectively. Similar plasma EC50 values for the inhibition of SERT (2.29–3.7 ng/ml) have been reported from human PET studies. This study illustrates the value of translational PK/PD modeling approaches and suggests that the preclinical modeling approach used in the current study is capable of predicting plasma concentrations associated with 50% occupancy of SERT in the human central nervous system.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.188417.

  • ABBREVIATIONS:

    5-HT
    5-hydroxytryptamine (serotonin)
    SERT
    serotonin transporter
    NE
    norepinephrine
    NET
    norepinephrine transporter
    MDD
    major depressive disorder
    PET
    positron emission tomography
    PK/PD
    pharmacokinetic/pharmacodynamic
    CNS
    central nervous system
    PBS
    phosphate-buffered saline
    CI
    confidence intervals
    V/F
    volume of the central compartment divided by oral bioavailability
    CV
    coefficient of variation
    DLX
    duloxetine.

  • Received September 26, 2011.
  • Accepted January 9, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleNeuropharmacology

PK/PD Modeling of Duloxetine Transporter Occupancy

David L. Bourdet, Pamela R. Tsuruda, Glenmar P. Obedencio and Jacqueline A. M. Smith
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 137-145; DOI: https://doi.org/10.1124/jpet.111.188417

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Research ArticleNeuropharmacology

PK/PD Modeling of Duloxetine Transporter Occupancy

David L. Bourdet, Pamela R. Tsuruda, Glenmar P. Obedencio and Jacqueline A. M. Smith
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 137-145; DOI: https://doi.org/10.1124/jpet.111.188417
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