Critical Analysis of Hepatic Clearance Based on an Advection Mass Transfer Model and Mass Balance.

The relationship between liver blood flow rate and hepatic clearance has been derived and validated based on the constitutive principle of mass conservation using an advective mass transfer model for bivariate concentration, Ci (x, t). Metabolic elimination continuously diminishes along the blood flow path line, corresponding with the concentration gradient. Because of the constraint introduced by constant blood velocity, x and t are not independent variables. This requires the introduction of a new factor called the dwell time, which accounts for the time a drug is retained in the liver. First-order or saturable drug metabolism is dependent on perfusate drug concentration and the dwell time. A new extraction factor is explicitly identified as E = ln Cin/Cout. Because the isolated organ perfusion model described here is validated, it provides a basis for drawing inferences and exploring underlying features, mechanisms, and principles on which this model is based. In the conventional model, these underlying constitutive principles are unavailable. The concentration-time profile of a physiological-based elimination network is found to be inconsistent with the profile described by a pharmacokinetic model. For this reason, among others discussed, physiological-based models are incompatible with pharmacokinetic models and therefore cannot be used to explain systemic pharmacokinetic behavior.