Effect of pregnancy or renal dysfunction on differences in plasma protein binding of phenytoin in peripheral blood and blood exiting the liver of rats

Abstract

The in vivo activity of hepatic drug metabolizing enzyme systems is reflected by the hepatic intrinsic metabolic clearance of drugs. The intrinsic hepatic clearance is determined on the basis of a drug’s total hepatic clearance as represented by the concentration changes (referable to the liver) of free plus protein-bound drug in blood, the fraction of that concentration which is not bound to proteins, and the hepatic blood perfusion rate (Wilkinson and Shand, 1975). If a substantial portion of drug in the blood is contained in or on the erythrocytes, the rate of release of drag from erythrocytes to plasma relative to the residence time of the blood in the liver may also have to be taken into consideration. It is customary, particularly in the case of relatively slowly cleared drugs, to determine the plasma or serum (rather than whole blood) clearance of a drug, either following administration of a bolus dose or at steady-state during constant rate infusion, by obtaining blood samples from a peripheral vein for measurement of drug concentrations and free fraction (protein binding) in plasma or serum. However, the plasma protein binding of drugs is often affected by the presence of endogenous binding inhibitors in the plasma, for example during pregnancy (Stock et al., 1980) and renal dysfunction (Craig et al., 1976; Sjiiholm et al., 1976), and it is possible that the concentration of these inhibitors, and therefore the protein binding of a drug, may be different in peripheral and hepatic blood. This can be so because the liver may extract some endogenous binding displacers from the circulation, an example being the substantial hepatic extraction of endogenous non-esterified fatty acids (Chou et al., 1983), and/or because the liver may form elidogenous displacers