Pharmacokinetic-pharmacodynamic analysis of the EEG effect of alfentanil in rats following beta-funaltrexamine-induced mu-opioid receptor "knockdown"in vivo
M. Garrido et al., Pharmacokinetic-pharmacodynamic analysis of the EEG effect of alfentanil in rats following beta-funaltrexamine-induced mu-opioid receptor "knockdown"in vivo, PHARM RES, 17(6), 2000, pp. 653-659
The objective of this investigation was to determine the influence of pre-t
reatment with the irreversible mu-opioid receptor antagonist beta-funaltrex
amine (P-FNA) on the pharmacokinetic-pharmacodynamic (PK/PD) relationship o
f alfentanil in rats.
Methods. The PK/PD correlation of alfentanil (2 mg.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.kg(-1)) either 35 min or 24 h pr
ior to the PK/PD experiments.
Results. Pre-treatment with beta-FNA had no influence on the pharmacokineti
cs of alfentanil. The in vivo concentration-EEG effect relationships, howev
er, were steeper and shifted towards higher concentrations with no differen
ce between the 35-min and the 24-h pre-treatment groups. Analysis of the da
ta on basis of the operational model agonism revealed that the observed cha
nges could be explained by a 70-80% reduction in alfentanil efficacy in bet
a-FNA pre-treated rats. This is consistent with results from an in vitro re
ceptor bioassay showing a 40-60% reduction in the number of specific mu-opi
oid binding sites in the brain.
Conclusion. This investigation confirms the validity of a previously postul
ated mechanism-based PK/PD model for the effect of synthetic opiates in rat
s.