The assessment of bioavailability in the presence of nonlinear elimination.

The simultaneous administration of an oral dose and intravenous tracer dose, as a method to determine bioavailability, was examined by means of computer simulation for drugs exhibiting Michaelis-Menten type elimination. A physiological pharmacokinetic model parameterized for man and including first-order absorption and elimination solely from the liver was employed. This tracer method provided good estimates of the true availability, with an error of 6% or less, over a wide range of dosing and dispositional conditions. Poorer estimates were noted when large doses of drugs with very short half-lives were considered. This poor performance was improved by administering the intravenous tracer at some time after the oral dose but an a priori basis for establishing this time was not apparent. The tracer method, therefore, appears to be a robust means of assessing, in man, oral bioavailability in the presence of Michaelis-Menten type elimination for drugs characterized by the general properties of the physiological model employed and with half-lives in excess of approximately 40 min. These findings together with the statistical power and simplicity of performance of the tracer method indicate that it is a valid technique for the assessment of bioavailability under a wide range of kinetic conditions.