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

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.