Pharmacokinetic-pharmacodynamic analysis of the EEG effect of alfentanil in rats following beta-funaltrexamine-induced mu-opioid receptor "knockdown" in vivo.
OBJECTIVE
The objective of this investigation was to determine the influence of pre-treatment with the irreversible mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) on the pharmacokinetic-pharmacodynamic (PK/PD) relationship of alfentanil in rats.


METHODS
The PK/PD correlation of alfentanil (2 mg x kg(-1) intravenously in 20 min) was determined in chronically instrumented rats using amplitudes in the 0.5-4.5 Hz frequency band of the EEG as pharmacodynamic endpoint. Beta-FNA was administered intravenously (10 mg x kg(-1)) either 35 min or 24 h prior to the PK/PD experiments.


RESULTS
Pre-treatment with beta-FNA had no influence on the pharmacokinetics of alfentanil. The in vivo concentration-EEG effect relationships, however, were steeper and shifted towards higher concentrations with no difference between the 35-min and the 24-h pre-treatment groups. Analysis of the data on basis of the operational model agonism revealed that the observed changes could be explained by a 70-80% reduction in alfentanil efficacy in beta-FNA pre-treated rats. This is consistent with results from an in vitro receptor bioassay showing a 40-60% reduction in the number of specific mu-opioid binding sites in the brain.


CONCLUSIONS
This investigation confirms the validity of a previously postulated mechanism-based PK/PD model for the effect of synthetic opiates in rats.
Garrido
M
M
Division of Pharmacology, Leiden Amsterdam Center for Drug Research, The Netherlands.
Gubbens-Stibbe
J
J
Tukker
E
E
Cox
E
E
von Frijtag
J
J
Künzel
D
D
IJzerman
A
A
Danhof
M
M
van der Graaf
P H
PH
D015760:Alfentanil / Q000493:pharmacokinetics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004569:Electroencephalography; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D015760:Alfentanil; D009271:Naltrexone; C024524:beta-funaltrexamine