Perfusion-limited effects of plasma drug binding on hepatic drug extraction

The hepatic elimination of phenytoin has been studied in the isolated rat liver perfused at constant flow with Krebs solution alone and in the presence of albumin. At an albumin concentration of 0.5 g/dl, 46.6% of the phenytoin was bound in the perfusate and the comparable value at 5.0 g/dl was 87.4%. The increase in binding resulted in a reduction in the hepatic extraction ratio from 0.67 in Krebs to 0.54 and 0.28 at the two albumin concentrations, respectively. Analysis of this data together with that from the literature on propranolol and warfarin indicated that they were consistent with the perfusion-limited model of hepatic clearance. Accordingly, the general relationship between the extraction ratio and the free fraction of drug in the blood is hyperbolic with the precise shape being determined by the ratio of the clearance of the drug from liver water to the hepatic blood flow rate.