Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung

Abstract

We measured the pulmonary venous concentration vs. time curves for [3H]alfentanil, [14C]lidocaine, and [3H]codeine after the bolus injection of each of these lipophilic amine compounds (LAC) and a vascular-reference indicator (fluorescein isothiocyanate-dextran) into the pulmonary artery of isolated perfused rabbit lungs. A range of flows and perfusate albumin concentrations was studied. To evaluate the information content of the data, we developed a kinetic model describing the pulmonary disposition of these LAC that was based on indicator dilution theory, and we sought a robust approach for interpreting the estimated model parameters. We found that the distribution of the kinetic model rate constants of the lipophilic amine-tissue interactions can be described by alpha, H, and psi, where alpha is a measure of the capacity of the rapidly equilibrating interactions between the lipophilic amine and the tissue; H is a measure of the equilibrium capacity of the slowly equilibrating interactions between the lipophilic amine and the tissue; and psi is the mean sojourn time. The values of alpha, H, and psi were 0.8 +/- 0.1 (SE), 0.6 +/- 0.1, and 1.6 +/- 0.5 s; 1.9 +/- 0.1, 5.3 +/- 0.4, and 5.6 +/- 0.5 s; and 1.1 +/- 0.1, 9.8 +/- 0.4, and 4.7 +/- 0.2 s for alfentanil, lidocaine, and codeine, respectively. These values for alpha, H, and psi reveal the relative dominance of the slowly equilibrating interactions for lidocaine and codeine in comparison with alfentanil. This approach to data analysis may have utility for the potential use of LAC to reveal and to quantify changes in lung tissue composition associated with lung disease.

Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity

“…The phenylephrineinduced increase in RD p 2 by 41% and decrease of V p by 17% is comparable to the changes of 75 and 15%, respectively, reported after hypoxic pulmonary vasoconstriction (7). Because Audi et al (1) have shown that a flow change per se does not change RD p 2 , the increase in relative dispersion by phenylephrine may be attributed to an increased heterogeneity of flow distribution. Because of the small interstitial space of the lungs (v p ϳ0.02) (20), whole body methods are not sensitive enough to detect differences in the pulmonary distribution volumes and relative dispersion of indicators.…”

“…This holds especially for the relative dispersion in the systemic circulation in relation to whole body distribution of indicators. The relative dispersion of vascular markers has mostly been estimated by using isolated perfused organs, such as the lung (1,6,14), heart (4), and liver (29), whereas distributed models of blood-tissue exchange have been used for permeating indicators (3). In contrast to the wide use of both classical compartment models (8,10,18) and recirculatory compartmental models (11,15,16), only incomplete attempts have been made in the past to study whole body distribution of solutes on the basis of TTDs (25,30,33).…”

Coenzyme Q1redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia

“…Virtually all of the injected CoQ 1 H 2 was recovered as CoQ 1 H 2 in the venous effluent in normoxic and hyperoxic lungs at both flows. The observation that the CoQ 1 H 2 outflow curves at two different flows (10 and 30 ml/min) were virtually superimposable when the time axis for each curve was normalized to vascular mean transit time is a hallmark of a substance that freely permeates tissues (i.e., "flow limited")(2,3,6,8).…”

Advection and Diffusion of Substances in Biological Tissues With Complex Vascular Networks

“…The advection and diffusion of a nonmetabolizing substance is modeled by Eq. (2): (2) where C is the concentration of the substance, v is the advective velocity vector field describing the motion of blood in the vascular network, and D is the molecular diffusion coefficient in the tissue. Here diffusion is isotropic and occurs homogeneously throughout intravascular as well as extravascular regions.…”

“…For example, Audi et al 1,2 have noted that the Crone-Renkin model and other axially distributed descriptions of tracer transport may lead to variations in estimates of parameters (such as permeability) with flow. A comparison of the behavior of an alternative model (our three-dimensional network model) to that of axial-distributed models, provides new insight into this issue.…”