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. Traditional pharmacokinetic studies do not characterize the initial appearance and recirculation peaks of arterial blood concentrations observable in the period of onset of drug action. Pulmonary uptake markedly affects the early arterial blood concentration history of some drugs. By using an innovative pharmacokinetic model that describes the simultaneous disposition of physiologic markers, indocyanine green (ICG) (intravascular space) and antipyrine (tissue water), the contribution of pulmonary uptake to a comprehensive description of drug disposition is now possible. The proposed work will describe, from the moment of injection and upon the kinetic framework of these inert markers, the disposition of anesthetic drugs with dissimilar pulmonary uptake. The first study will further develop a model including initial drug distribution that delineates the contribution of pulmonary tissue distribution by describing the simultaneous disposition of ICG, antipyrine, and either lidocaine, fentanyl, or thiopental in dogs anesthetized with halothane. This multicompartmental model includes discontinuities between compartments which are arranged as parallel systemic circuits in series with a central (pulmonary) circuit in a recirculatory configuration. This model accounts for circulatory and tissue transit delays as well as a discrete pulmonary extravascular tissue compartment. These modeling techniques will then be used to study pulmonary drug uptake in human volunteers. In the first study, the affect of differential pulmonary uptake characteristics of alfentanil and fentanyl on their complete pharmacokinetic profiles will be studied. In the second study, the possible differential affect of propranolol, which competitively displaces other drugs from pulmonary distribution sites, on the pulmonary distribution of alfentanil and fentanyl will be studied.
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