• E H Cox, J A Kuipers, and M Danhof.
• Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Sylvius Laboratory, The Netherlands.
• Br. J. Pharmacol. 1998 Aug 1; 124 (7): 1534-40.

Abstract1. The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological effect relationship of alfentanil in rats using quantitative EEG parameters as a pharmacodynamic 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 continuously recorded and frequent arterial blood samples were collected for determination 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 45+/-3 ml x min(-1) x kg(-1), 0.91+/-0.09 l/kg(-1) and 23+/-1 min, respectively, 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 measure of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG effect relationships of alfentanil were derived which were successfully quantified by the sigmoidal Emax pharmacodynamic model. When the results of the first of the two consecutive infusions were compared, no systematic differences in the pharmacodynamic parameters were observed for the different infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean+/-s.e., n=20): E0=56+/-3 microV, Emax=93+/-8 microV, EC50=235+/-27 ng x ml(-1) and Hill factor=1.6+/-0.1, respectively. For the second of the two consecutive infusions a significantly higher value of the EC50 of 404+/-56 ng x ml(-1) was observed (P < 0.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration effect relationship can be explained by a 40% loss of functional mu-opioid receptors. 4. The results of the present study show that upon the administration of a single intravenous dose, acute functional adaptation does not interfere with the assessment of the concentration-EEG effect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

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