PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE EEG EFFECT OF ALFENTANIL IN RATS - ASSESSMENT OF RAPID FUNCTIONAL ADAPTATION

1 The purpose of the present investigation was to quantify rapid funct ional adaptation in the concentration-pharmacological effect relations hip of alfentanil in rats using quantitative EEG parameters as a pharm acodynamic endpoint. Three groups of 6-7 rats received in a randomized fashion two consecutive infusions of 2.00, 3.14. or 4.24 mg/kg(-1) of alfentanil in 20, 40 or 60 min, respectively. The EEG was continuousl y recorded and frequent arterial blood samples were collected for dete rmination of the alfentanil concentration by gas chromatography. 2 The pharmacokinetics of alfentanil were most adequately described by a bi -exponential function. The values (mean +/- s.e., n = 20) of clearance , volume of distribution at steady-state and terminal half-life were 4 5+/-3ml.min(-1).kg(-1), 0.91+/-0.09 l/kg(-1) and 23+/-1 min, respectiv ely, and independent of the administered dose. 3 Increase in power in the 0.5-4.5 Hz (delta) frequency band of the EEG was used as the measu re of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG effect relationships of alf entanil were derived which were successfully quantified by the sigmoid al E-max pharmacodynamic model. When the results of the first of the t wo consecutive infusions were compared, no systematic differences in t he pharmacodynamic parameters were observed for the different infusion rates. The averaged values of the pharmacodynamic parameters of alfen tanil were (mean+/-s.e., n = 20): E-0 = 56 +/- 3 mu V, E-max = 93 +/- 8 mu V, EC50 = 235+/-27 ng.ml(-1) and Hill factor = 1.6 +/- 0.1, respe ctively. For the second of the two consecutive infusions a significant ly higher value of the EC50 of 404 +/- 56 ng.ml(-1) was observed (P < 0.05), while the values of the other pharmacodynamic parameters were u nchanged. Simulations according to a mechanism-based model indicated t hat the observed change in concentration effect relationship can be ex plained by a 40% loss of functional mu-opioid receptors. 4 The results of the present study show that upon the administration of a single in travenous dose, acute functional adaptation does not interfere with th e assessment of the concentration-EEG effect relationship of alfentani l. Upon repeated administration however functional adaptation may be a complicating factor.