Inhalation pharmacokinetics based on gas uptake studies - I. Improvement of kinetic models

An improved pharmacokinetic model is described for inhalation of volatile xenobiotics from a closed gas phase system. This model is based on steady-state kinetics and covers metabolic elimination processes of either first-order, zero-order, or Michaelis-Menten characteristics. It is emphasized that the distribution of a volatile compound between gas phase and organism under steady-state conditions may be much different from a static equilibrium obtained in absence of metabolism, as it is observed after application of a metabolic inhibitor. A re-analysis of previous experimental data on dose-dependent pharmacokinetics of different haloethylenes reveals that, in general, the metabolic elimination processes of the rapidly equilibrating mono-haloethylenes (and vinylidene fluoride) can be resolved with excellent accuracy into sections of first-order and zero-order kinetics. Other compounds show a more smooth transition from first-order elimination (at lower atmospheric concentrations) into conditions of saturation (dichloroethylenes, trichloroethylene). The analyses are consistent with a recent concept of Andersen (1980) that metabolic elimination of inhaled xenobiotics is limited by either the capacity of metabolic enzymes or factors of transport to the metabolic sites.