Covalent and Noncovalent Protein Binding of Drugs: Implications for Hepatic Clearance, Storage, and Cell-Specific Drug Delivery

Abstract

This review deals with the mechanisms by which the liver disposes of drugs that are covalently or noncovalently associated with proteins. Many drugs bind to plasma proteins such as albumin (mainly anionic compounds) and α₁-acid glycoprotein (cationic compounds). Nevertheless, the liver is able to clear such drugs efficiently from the circulation because of intrahepatic dissociation of the drug-protein complex. This clearance may involve spontaneous dissociation because of progressive removal of the unbound drug during liver passage, a process that can be rate limiting in hepatic uptake. Alternatively, the porous endothelial lining of the hepatic sinusoids may allow extensive surface interactions of the drug–protein complexes with hepatocytes, leading to facilitation of drug dissociation. Binding to plasma proteins and intracellular proteins in the cytoplasm or cell organelles is an important factor determining the hepatic storage and elimination rate of drugs. Drugs noncovalently associated with glycosylated proteins, which can be endocytosed by various liver cells, are not co-endocytosed with such proteins. However, covalently bound drugs can be internalized by receptor-mediated endocytosis, which permits specific targeting to hepatocytes, endothelial cells, Kupffer cells, and lipocytes by coupling to different glycoproteins that are recognized on the basis of their terminal sugar. The endocytosed drug–carrier complex is routed into endosomes and lysosomes, where the active drug is liberated by cleavage of acid-sensitive linkages or proteolytic degradation of peptide linkers. This concept has been applied to antineoplastic, antiparasitic, and antiviral drugs.