ISSN:
1573-904X
Keywords:
alfentanil
;
β-funaltrexamine
;
μ opioid receptors
;
operational model of agonism
;
pharmacokinetic-pharmacodynamic modeling
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007513812018
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