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OtherANALGESIA AND DRUGS OF ABUSE

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Synthetic Opioids in the Rat: Correlation with the Interaction at the Mu-Opioid Receptor

Eugène H. Cox, Thomas Kerbusch, Pieter H. Van der Graaf and Meindert Danhof
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 1095-1103;
Eugène H. Cox
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Thomas Kerbusch
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Pieter H. Van der Graaf
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Meindert Danhof
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Abstract

The purpose of our investigation was to characterize the relationships between the pharmacodynamics of synthetic opioids in vivoand the interaction at the mu-opioid receptor. The pharmacokinetics and pharmacodynamics were determined in vivo after a single i.v. infusion of 3.14 mg/kg alfentanil (A), 0.15 mg/kg fentanyl (F) or 0.030 mg/kg sufentanil (S) in rats. Amplitudes in the 0.5 to 4.5 Hz frequency band of the electroencephalogram (EEG) was used as pharmacodynamic endpoint. The EEG effect intensity was related to the (free) concentration in blood (A) or in a hypothetical effect compartment (F, S) on basis of the sigmoidal Emax pharmacodynamic model. The interaction at the mu-opioid receptor was determined in vitro on basis of the displacement of [3H]-naloxone binding in washed rat brain membranes. The value of the sodium shift was used as a measure of in vitro intrinsic efficacy. For the EEG effect the in vivo potencies based on free drug concentrations (EC50,u) were 4.62 ± 0.66 ng/ml (A), 0.69 ± 0.05 ng/ml (F) and 0.29 ± 0.06 ng/ml (S). In the receptor binding studies the affinities at the mu-opioid receptor ( KI) were 47.4 ± 6.6 nM (A), 8.6 ± 4.1 nM (F) and 2.8 ± 0.2 nM (S). For each opioid the ratio between EC50,u and KI was the same with a value of 0.23–0.25, indicating the existence of receptor reserve for the EEG effect. The intrinsic activity (Emax) of the three opioids in vivo was similar with values of 111 ± 10 μV (A), 89 ± 11 μV (F) and 104 ± 4 μV (S). However, the values of the sodium shift varied between 2.8 (S) and 19.1 (A). Further analysis of the in vivo pharmacodynamic data on basis of an operational model of agonism provided evidence for a large receptor reserve, which explains why compounds with different values of the sodium shift all behave as full agonists in vivo.

Footnotes

  • Send reprint requests to: Dr. Meindert Danhof, Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, Sylvius Laboratory, P.O. Box 9503, 2300 RA Leiden, The Netherlands.

  • Abbreviations:
    PK/PD
    modeling-pharmacokinetic-pharmacodynamic modeling
    EEG
    electroencephalogram
    CNS
    central nervous system
    SPF
    specific pathogen free
    I-E ratio
    inspiration expiration ratio
    pCO2
    partial CO2 pressure
    pO2
    partial O2 pressure
    GC
    gas chromatography
    ID
    internal diameter
    HPLC
    high pressure liquid chromatography
    E0
    no drug effect
    Emax
    maximum drug effect
    EC50
    concentration resulting in 50% of the maximum drug effect
    ANOVA
    analysis of variance
    Cl
    total body clearance
    Vd,ss
    volume of distribution at steady-state
    t1/2,αn
    half-life associated with the nth exponential phase
    RIA
    radioimmunoassay, fu, fraction of drug concentration unbound in the body
    • Received July 21, 1997.
    • Accepted November 13, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherANALGESIA AND DRUGS OF ABUSE

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Synthetic Opioids in the Rat: Correlation with the Interaction at the Mu-Opioid Receptor

Eugène H. Cox, Thomas Kerbusch, Pieter H. Van der Graaf and Meindert Danhof
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1095-1103;

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OtherANALGESIA AND DRUGS OF ABUSE

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Synthetic Opioids in the Rat: Correlation with the Interaction at the Mu-Opioid Receptor

Eugène H. Cox, Thomas Kerbusch, Pieter H. Van der Graaf and Meindert Danhof
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1095-1103;
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