Hepatic clearance of drugs. III. Additional experimental evidence supporting the "well-stirred" model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused rat liver in situ preparation.

Abstract

The disposition of monoethylglycine xylidide (MEGX), a metabolite of lidocaine, was studied in the perfused rat liver in situpreparation in an attempt to further discriminate between two models of hepatic drug clearance. In the “well-stirred” model, the liver is regarded as a well-stirred compartment with the emergent drug concentration in equilibrium with that in the liver. In the “parallel tube” model, the liver is viewed as a series of indentical paralllel units with enzymes distributed evenly around the units. Using a single-passage perfusate system, we found in a previous study that the extraction ratio of lidocaine was maximal and constant (0.997) below 7 mg/liter. The steady-state output MEGX concentration appearing in the emergent blood upon a constant and low-input concentration of lidocaine (4 mg/liter) was determined under varying hepatic blood flow rates (10–16 ml/min per liver). The data suggest that operationally the “well-stirred” model adequately describes the appearance of MEGX from lidocaine.