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PURPOSE: 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.