First Pass Uptake in the Human Lung of Drugs Used during Anesthesia

Abstract

This chapter focuses on understanding the extent and character of uptake of drugs, both in the human lung and in isolated perfused animal lung preparations. It is well established that the pulmonary circulation has important functions other than gas exchange. This includes a pharmacokinetic function in which cells of the pulmonary endothelium have been shown to accumulate a wide variety of biogenic and xenobiotic substances. The lung can play an important role in regulating the arterial blood concentrations of compounds that exhibit high pulmonary accumulation. The pulmonary circulation is capable of a very rapid and extensive extraction of certain drugs from the blood during a single transit through the lung after intravenous administration of the drug bolus. The extent of uptake depends on the physicochemical characteristics of the drug and its binding affinity to plasma proteins and lung tissue. Any factor that alters plasma protein binding of a drug could alter the partitioning of the drug between the plasma and lung tissue. For some basic lipophilic amines the high first pass uptake in the human lung controls the initial rate of entry of the major portion of the dose into the systemic circulation and plays a complex role in moderating plasma drug concentrations during the early distributional phase of plasma pharmacokinetics. The extent of first pass uptake in the lung also predicts the relative magnitude of the lung as a tissue reservoir of the drug at later times after administration during the dispositional phase of the pharmacokinetics of the drugs. Pulmonary uptake kinetics can reflect the effect of rate process such as association and dissociation from plasma protein and diffusion rates. The fact that the pulmonary capillary bed accumulates so many different drugs presents an opportunity for using these therapeutic agents as indicators in multiple indicator dilution studies of the pulmonary circulation in humans.