BackgroundNew gas therapies using inert gases such as xenon and argon are being studied, which would require chronically administered repeating doses. The pharmacokinetics of this type of administration has not been addressed in the literature.MethodsA physiologically based pharmacokinetics (PBPK) model for humans, pigs, mice, and rats has been developed to investigate the unique aspects of the chronic administration of inert gas therapies. The absorption, distribution, metabolism and excretion (ADME) models are as follows: absorption in all compartments is assumed to be perfusion limited, no metabolism of the gases occurs, and excretion is only the reverse process of absorption through the lungs and exhaled.ResultsThe model has shown that there can be a residual dose, equivalent to constant administration, for chronic repeated dosing of xenon in humans. However, this is not necessarily the case for small animals used in pre-clinical studies.ConclusionsThe use of standard pharmacokinetics parameters such as area under the curve would be more appropriate to assess the delivered dose of chronic gas administration than the gas concentration in the delivery system that is typically reported in the scientific literature because species and gas differences can result in very different delivered doses.

New gas therapies using inert gases such as xenon and argon are being studied, which require in vitro and in vivo preclinical experiments. Examples of the kinetics of gas transport during such experiments are analyzed in this paper. Using analytical and numerical models, we analyze an in vitro experiment for gas transport to a 96 cell well plate and an in vivo delivery to a small animal chamber, where the key processes considered are the wash-in of test gas into an apparatus dead volume, the diffusion of test gas through the liquid media in a well of a cell test plate, and the pharmacokinetics in a rat. In the case of small animals in a chamber, the key variable controlling the kinetics is the chamber wash-in time constant that is a function of the chamber volume and the gas flow rate. For cells covered by a liquid media the diffusion of gas through the liquid media is the dominant mechanism, such that liquid depth and the gas diffusion constant are the key parameters. The key message from these analyses is that the transport of gas during preclinical experiments can be important in determining the true dose as experienced at the site of action in an animal or to a cell.

Under normal conditions we continuously breathe 78% nitrogen (N2) such that the body tissues and fluids are saturated with dissolved N2. For normobaric medical gas administration at high concentrations, the N2 concentration must be less than that in the ambient atmosphere; therefore, nitrogen will begin to be released by the body tissues. There is a need to estimate the time needed for denitrogenation in the planning of surgical procedures. In this paper we will describe the application of a physiologically based pharmacokinetic model to denitrogenation kinetics. The results are compared to the data resulting from experiments in the literature that measured the end tidal N2 concentration while breathing 100% oxygen in the form of moderately rapid and slow compartment time constants. It is shown that the model is in general agreement with published experimental data. Correlations for denitrogenation as a function of subject weight are provided.