Protein binding and hepatic clearance: Discrimination between models of hepatic clearance with diazepam,a drug of high intrinsic clearance,in the isolated perfused rat liver preparation

The influence of protein binding on the extraction ratio, and availability, of diazepam has been examined in the single-pass isolated perfused rat liver preparation. Binding of diazepam was varied by adjusting the concentration of albumin in the perfusate. In the absence of binding the extraction ratio of diazepam was high, 0.93–0.995. Extraction decreased dramatically as the degree of binding was increased. The data are more consistent with the parallel-tube model than with the well-stirred model, two perfusion models that have been used to describe hepatic drug elimination.