Susan B. Ahlf

First pass uptake of fentanyl, meperidine, and morphine in the human lung

The first pass uptake of fentanyl, meperidine, and morphine in human lung was studied in patients using a double indicator dilution technique. A bolus containing one of the drugs and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia for surgery. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of drug taken up by the lung during the first pass and the instantaneous extraction of drug at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. The total uptake (mean ± SE) during the first pass through the human lung for fentanyl and meperidine was 75.2 ± 3.2% and 64.7 ± 7.8% of the injected dose, respectively. The pulmonary uptake of morphine was very small, with 96.5 ± 7.1% of the injected dose recovered in arterial blood after the first pass through the lung. The arterial blood concentration of drug and dye versus time showed a slight delay of the fentanyl and meperidine peaks compared to ICG, It was also observed that greater than 90% of these drugs were extracted from the blood in the early part of the first pass, but the extraction decreased with time during the first pass through the lung. These findings indicate that sonic of the drug taken up by the lung can diffuse back out into the blood. In spite of this back diffusion, 75% and 65% of the fentanyl and meperidine remained in the lung tissue at the end of the first pass. This high first pass pulmonary uptake of fentanyl and meperidine results in a large decrease in the amount of drug that enters the systemic circulation immediately after injection. This non-respiratory pulmonary function could play a major role in determining the plasma pharmacokinetics of these drugs immediately after intravenous administration. No such role of the lung exists for morphine.

First-pass uptake of verapamil, diazepam, and thiopental in the human lung

The first-pass uptake of verapamil, diazepam, and thiopental in the human lung was determined using multiple-indicator dilution techniques. These three drugs represent lipid-soluble agents that differ in their ionic characteristics at physiological pH. Verapamil, a basic lipophilic amine, underwent significant uptake, with 50% of the drug accumulating in lung tissue during the first pass. With diazepam, a nonbasic lipophilic amine, there was 30% uptake during the first pass through the human lung-significantly less than that observed with verapamil. With thiopental, an acidic lipophilic barbiturate, only 14% of the injected drug accumulated in the lung during the first pass. Taken together, these data are consistent with observations from animal studies, which indicate that extensive pulmonary uptake is greater with basic amine drugs that are moderately to highly lipid-soluble. Also, the relatively high first-pass uptake of verapamil in the human lung suggests a quantitatively significant role of this nonrespiratoy function of the lung in the early pharmacokinetics of intravenous verapamil.

Precursors and inhibitors of hydrogen sulfide synthesis affect acute hypoxic pulmonary vasoconstriction in the intact lung

The effects of hydrogen sulfide (H(2)S) and acute hypoxia are similar in isolated pulmonary arteries from various species. However, the involvement of H(2)S in hypoxic pulmonary vasoconstriction (HPV) has not been studied in the intact lung. The present study used an intact, isolated, perfused rat lung preparation to examine whether adding compounds essential to H(2)S synthesis or to its inhibition would result in a corresponding increase or decrease in the magnitude of HPV. Western blots performed in lung tissue identified the presence of the H(2)S-synthesizing enzymes, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), but not cystathionine β-synthase (CBS). Adding three H(2)S synthesis precursors, cysteine and oxidized or reduced glutathione, to the perfusate significantly increased peak arterial pressure during hypoxia compared with control (P < 0.05). Adding α-ketoglutarate to enhance the 3-MST enzyme pathway also resulted in an increase (P < 0.05). Both aspartate, which inhibits the 3-MST synthesis pathway, and propargylglycine (PPG), which inhibits the CSE pathway, significantly reduced the increases in arterial pressure during hypoxia. Diethylmaleate (DEM), which conjugates sulfhydryls, also reduced the peak hypoxic arterial pressure at concentrations >2 mM. Finally, H(2)S concentrations as measured with a specially designed polarographic electrode decreased markedly in lung tissue homogenate and in small pulmonary arteries when air was added to the hypoxic environment of the measurement chamber. The results of this study provide evidence that the rate of H(2)S synthesis plays a role in the magnitude of acute HPV in the isolated perfused rat lung.

Effect of Propranolol on the First Pass Uptake of Fentanyl in the Human and Rat Lung

The first pass uptake of fentanyl in the human lung was studied in two groups of patients using a double indicator dilution technique. A bolus containing fentanyl and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of fentanyl taken up by the lung during the first pass and the instantaneous extraction of fentanyl at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. In patients who had been receiving no other drugs prior to the experiment, the total first pass uptake (mean +/- SE) of fentanyl was 82.6% +/- 1.4% of the injected dose. In patients who had been receiving 30-120 mg/day of propranolol the total first pass uptake (mean +/- SE) of fentanyl decreased to 52.8% +/- 6.3% of the injected dose. In one patient on 120 mg of propranolol per day, first pass uptake of fentanyl was only 20.3% of the injected dose. Additional studies in a rat isolated perfused lung preparation coperfused with fentanyl and propranolol also demonstrated that one basic lipophilic amine (propranolol) could inhibit the pulmonary uptake of a second basic lipophilic amine (fentanyl). The high first pass uptake of fentanyl in the human lung limits the rate of entry of this drug into the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

An Interpretation of 14C-Urea and 14C-Primidone Extraction in Isolated Rabbit Lungs

We measured the venous concentration versus time curves of14C-urea and14C-primidone after rapid bolus injections of a vascular reference indicator, fluorescein isothiocyanate dextran, and one of the two14C-labeled indicators in isolated rabbit lungs perfused with Krebs-Ringer bicarbonate solution containing 4.5% bovine serum albumin at flow rates (F) of 6.67, 3.33, 1.67, and 0.83 ml/sec and with nearly constant microvascular pressure and total lung vascular volume. When we calculated the permeability-surface area product,PS, from the14C-urea and14C-primidone outflow curves using the Crone model, the estimates of thePS product were directly proportional toF. However, the fractional change in thePS with flow was different for the two indicators. We also estimated thePS from the same14C-urea and14C-primidone data using an alternative model that includes perfusion heterogeneity, estimated in a previous study, and flow-limited and barrier-limited extravascular volumes accessible to both urea and primidone. This model was able to fit the outflow curves of either14C-urea or14C-primidone at all four flows studied with one flow-independentPS for each indicator. The ability of the new model to explain the14C-urea and14C-primidone data with no flow-dependent change inPS suggests that a change inPS withF estimated using other models such as the Crone model is not sufficient evidence for capillary surface area recruitment.

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

Publisher Summary 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.

Lipophilic Amines as Probes for Measurement of Lung Capillary Transport Function and Tissue Composition Using the Multiple-Indicator Dilution Method

We have exploited the rapidly equilibrating interactions of nonbasic lipophilic amines such as l4C-diazepam and 3H-alfentanil with lung tissue to estimate the perfused lung tissue water/lipoid space ratio, and to develop a method for estimating the pulmonary capillary transit time distribution using the bolus-injection multiple-indicator dilution technique.