title: Pharmacokinetic-pharmacodynamic modelling of the EEG effect of alfentanil in rats.
abstract: The purpose of the present investigation was to develop a methodology for quantification of the concentration-pharmacological effect relationship of alfentanil in individual rats by using effect parameters derived from quantitative EEG analysis. In particular, the role of the opioid-induced side effects of proconvulsant activity, hypothermia, and respiratory depression was investigated. Amplitudes in the 0.5- to 4.5-Hz frequency band of the EEG power spectrum were used as a descriptor of the effect. The pharmacokinetics and pharmacodynamics of alfentanil were determined after intravenous administration of 2000 micrograms/kg during 20 min. The administration of alfentanil induced paroxysmal seizure patterns in the EEG which made meaningful analysis of the EEG effect impossible. A constant infusion of midazolam (5.5 mg/kg/hr) prevented alfentanil-induced seizures. When no precautions were taken to control body temperature, analysis of the concentration-EEG effect relationship was complicated by proteresis due to alfentanil-induced hypothermia. This proteresis disappeared when body temperature was stabilized at 37.5 degrees-38.5 degrees C with isothermal pads. Alfentanil-induced respiratory depression was managed successfully by artificial ventilation. Adequateness of artificial ventilation was ascertained by monitoring of arterial pO2, pCO2, and pH. When these opioid side effects were controlled, the pharmacokinetics were most adequately described by a biexponential function. The values of the pharmacokinetic parameters were (mean +/- SE, n = 7); clearance = 53 +/- 6 ml.min/kg, volume of distribution = 1.19 +/- 0.19 l/kg and terminal half-life = 24.5 +/- 2.3 min. By pharmacokinetic-pharmacodynamic modelling, the individual concentration-effect relationships of alfentanil were derived, which were successfully characterized by the sigmoidal Emax pharmacodynamic model. The values of the pharmacodynamic parameters were (mean +/- SE, n = 7): E0 = 57 +/- 4 microV, Emax = 95 +/- 17 microV, EC50 = 202 +/- 55 ng/ml and Hill factor = 1.53 +/- 0.20. No delay was observed between alfentanil concentration and effect. The results of the present study show that when side effects are controlled adequately, the concentration-EEG effect relationship of alfentanil can be characterized in individual rats using amplitudes in the 0.5- to 4.5-Hz frequency band of the EEG as a measure of the pharmacological response. The described methodology can be very useful for detailed studies into the pharmacodynamics of (new) synthetic opioids in vivo.
authors.affiliation: Division of Pharmacology, Leiden, Center for Drug Research, University of Leiden, Sylvius Laboratory, The Netherlands.
authors.forename: E H
authors.initials: EH
authors.lastname: Cox
authors.forename: J G
authors.initials: JG
authors.lastname: Van Hemert
authors.forename: E J
authors.initials: EJ
authors.lastname: Tukker
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D015760:Alfentanil / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001784:Blood Gas Analysis; D001831:Body Temperature / Q000187:drug effects; D002849:Chromatography, Gas; D004569:Electroencephalography / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012121:Respiration, Artificial; D012640:Seizures / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; D015760:Alfentanil