Pharmacokinetic-Pharmacodynamic Analysis of the EEG Effect of Alfentanil in Rats Followingβ-Funaltrexamine-Induced μOpioid Receptor “Knockdown”In Vivo (original) (raw)

Abstract

Purpose. The objective of this investigation was to determine theinfluence of pre-treatment with the irreversible μ-opioid receptorantagonist β-funaltrexamine (β-FNA) on thepharmacokinetic-pharmacodynamic (PK/PD) relationship of alfentanil in rats.

Methods. The PK/PD correlation of alfentanil (2 mg.kg−1intravenously in 20 min) was determined in chronically instrumented ratsusing amplitudes in the 0.5–4.5 Hz frequency band of the EEG aspharmacodynamic endpoint. β-FNA was administered intravenously(10 mg.kg−1) either 35 min or 24 h prior to the PK/PD experiments.

Results. Pre-treatment with β-FNA had no influence on thepharmacokinetics of alfentanil. The in vivo concentration-EEG effectrelationships, however, were steeper and shifted towards higher concentrationswith no difference between the 35-min and the 24-h pre-treatmentgroups. Analysis of the data on basis of the operational model agonismrevealed that the observed changes could be explained by a 70–80%reduction in alfentanil efficacy in β-FNA pre-treated rats. This isconsistent with results from an in vitro receptor bioassay showing a40–60% reduction in the number of specific μ-opioid binding sites inthe brain.

Conclusions. This investigation confirms the validity of a previouslypostulated mechanism-based PK/PD model for the effect of syntheticopiates in rats.

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  1. Division of Pharmacology, Leiden Amsterdam Center for Drug Research, P.O. Box 9503, 2300 RA, Leiden, The Netherlands
    >Maria Garrido, Josy Gubbens-Stibbe, Erica Tukker, Eugégne Cox, Jacobien von Frijtag & Piet H. van der Graaf
  2. Division of Medicinal Chemistry, Leiden Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA, Leiden, The Netherlands
    Jacobien von Frijtag, DrabbeM Künzel & Ad IJzerman
  3. Discovery Biology, Pfizer Central Research, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
    Jacobien von Frijtag & Piet H. van der Graaf
  4. Division of Pharmacology, Leiden Amsterdam Center for Drug Research, P.O. Box 9503, 2300 RA, Leiden, The Netherlands
    Jacobien von Frijtag & Meindert Danhof

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Garrido, >., Gubbens-Stibbe, J., Tukker, E. et al. Pharmacokinetic-Pharmacodynamic Analysis of the EEG Effect of Alfentanil in Rats Followingβ-Funaltrexamine-Induced μOpioid Receptor “Knockdown”In Vivo.Pharm Res 17, 653–659 (2000). https://doi.org/10.1023/A:1007513812018

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