The influence of binding to albumin and alpha 1-acid glycoprotein on the clearance of drugs by the liver

Abstract

The liver is a major site for synthesis and catabolism of plasma proteins. Albumin has various binding sites for anionic drugs, alpha 1-acid glycoprotein possesses a single binding site for cationic drugs. In spite of extensive protein binding, the liver can efficiently remove drugs from the circulation. Intrahepatic dissociation of the drug-protein complex may involve dissociation-limited debinding under non-equilibrium conditions or surface interaction-facilitated dissociation phenomena. During liver or renal disease and acute-phase conditions plasma protein binding of drugs may be affected. Changes in the unbound drug fraction do not always result in proportional changes in clearance or distribution volume. Potential changes in the unbound concentration in steady-state as well as the fluctuations in total plasma levels depend on the extent of protein binding of a drug, the relative change in the unbound drug fraction type of clearance, the size of the distribution volume, route of administration as well as concomitant changes in intrinsic (cellular) clearance function. Optimization of dosage regimens for certain drugs and interpretation of liver function tests with diagnostic dyes may largely benefit from determination of the unbound rather than the total concentration of the drugs involved.