Models of hepatic drug clearance: discrimination between the ‘well stirred’ and ‘parallel-tube’ models

Abstract

The predictive ability of two models of hepatic drug clearance are compared. The ‘parallel‐tube’ model predicts that the steady‐state drug concentration following constant rate oral administration increases with increase in hepatic blood flow. The ‘well‐stirred’ model predicts that this parameter is not sensitive to changes in hepatic blood flow. Using the steady‐state reservoir drug concentration as the discriminatory index, the predictions of the models were tested in a recirculating isolated perfused rat liver system with lignocaine and pethidine, both of which are highly extracted, as test drugs. The steady‐state reservoir concentration of both drugs was found to be constant when flow through the liver was increased from 10 ml min⁻¹ to 15 ml min⁻¹. The experimental findings indicate that the ‘well‐stirred’ model more accurately describes the elimination of highly cleared drugs with perturbations of flow than does the ‘parallel‐tube’ model.