The long term objective of this research program is to improve the understanding of the dose-response relationships of rapidly acting intravenous anesthetics by describing anatomic and physiologic factors affecting their pharmacokinetics and pharmacodynamics. The effect of propranolol pretreatment on both the pulmonary uptake and the pharmacodynamics of fentanyl will be determined in man in order to quantitate the pharmacokinetics of this interaction and to determine whether any pharmacodynamic changes are the result of either reduced fentanyl pulmonary uptake or primary changes at the effects site, as delineated by altered ke0 and EC50, or both. Combined recirculatory multicompartmental pharmacokinetic-pharmacodynamic models will be constructed based on the continuous measure of the effect of fentanyl on the EEG and on pupil diameter. The importance of pulmonary drug uptake to pharmacodynamic effect of fentanyl will be further tested by comparing the disposition and EEG effects of fentanyl when injected into the right atrium to those when injected into the left ventricle in untreated dogs and in dogs pretreated with propranolol. Combined recirculatory multicompartmental pharmacokinetic-pharmacodynamic models will then be constructed based on the continuous measure of the effect of fentanyl on the EEG. In vitro methods for evaluating tissue drug distribution will compare the uptake of drugs with known degrees of pulmonary uptake in isolated perfused canine lungs with that in pulmonary endothelial cell culture system. The effect of drug interactions on tissue drug uptake will also be studied in these systems because recirculation obscures kinetic detail for drugs with the greatest pulmonary uptake, hence longer pulmonary transit times.
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