Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model

BACKGROUND: New 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. METHODS: A 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. RESULTS: The 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. CONCLUSIONS: The 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.