Drug Interactions at Plasma and Tissue Binding Sites

Abstract

The binding of drugs to plasma and tissue proteins is a major determinant of drug distribution throughout the body. This binding has also a very important effect on drug dynamics since it is only the free (unbound) drug which can diffuse to, and interact with, receptor sites, i.e., bound drug is pharmacologically inactive. The relative ease of study in vitro of the binding of drugs in human plasma and in separate protein fractions (mainly albumin) has led to an extensive literature on the subject, with the influence of other drugs and/or endogenous materials on drug binding being a common topic for investigation. The relative difficulty in obtaining samples of viable human tissues has meant that work on the binding of drugs to human tissues has been very limited by comparison, although this may change with the more widespread use of tissue culture techniques. It is as a result of this large body of largely in vitro data that the topic of protein binding displacement interactions has gained prominence as a possible mechanism of drug-drug interactions; however, as mentioned in Chap. 1 of this volume, the importance of plasma protein binding displacement interactions has been overestimated and overstated and only in very specific cases do they result in adverse outcomes. In this chapter the influence of plasma and tissue binding on drug kinetics is discussed to facilitate consideration of the consequences of drug displacement from binding sites and their possible clinical significance. Those cases in which displacement can lead to clinically significant outcomes, which are much more restrictive than much of the literature and popular belief amongst practitioners would suggest, are considered in some detail. Before moving on the these issues, the proteins involved in drug binding are described.KeywordsValproic AcidTherapeutic Drug MonitoringPlasma Protein BindingTissue BindingFree Drug ConcentrationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.