Chapter 33. Plasma Protein Binding of Drugs

Abstract

Publisher Summary The role of plasma protein binding is recognized as an important factor in drug disposition and efficacy. This chapter discusses the structures of drug-binding proteins, particularly human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG), the relationship between ligand structure and protein binding and the effect of plasma protein binding on drug disposition and pharmacological activity. Human serum albumin (HSA) binds a wide variety of endogenous and exogenous ligands with association constants typically in the range of 10 4 to 10 6 M –1 . As the most abundant protein in plasma, it plays an important role in the maintenance of blood pH and colloidal osmotic pressure and accounts for most of the thiol content of plasma. Numerous competition and spectroscopic studies, using various ligands, have identified two sites (I and II) most relevant for drug binding. The interaction of various nonsteroidal anti-inflammatory drugs (NSAIDs) with HSA has been studied extensively. The interaction of other drug classes with HSA has also been investigated. Covalent modification of plasma proteins can be produced by direct attachment of an electrophilic moiety of the parent molecule to nucleophilic protein residues or by metabolic activation of the parent to a more reactive species. These reactions are important as their potential to form immunogenic adducts, with the possibility of producing idiosyncratic hypersensitivity reactions. Microdialysis is a potent technique to measure the extent of binding in vivo or in vitro in plasma. high-performance liquid chromatography (HPLC) methods, utilizing protein stationary phases, offer the potential for rapid screening, especially for those molecules bound to albumin. The blood brain barrier (BBB) effectively restricts the access of polar, hydrophilic drugs into the central nervous system (CNS), thus establishing a significant drug delivery impediment.