Protein binding drug displacement interactions fact or fiction

A drug displacement interaction is loosely defined as the reduction in extent of plasma protein binding of one drug caused by the presence of another drug. These interactions may be caused by competition between the drugs involved for a common binding site (competitive inhibition) or by the ability of the displacer to alter tertiary conformation of the binding protein (non-competitive inhibition). Regardless of the mechanism, the end result is an increased unbound fraction of the displaced drug. In most early reports of adverse drug interactions that were known to involve binding displacement, observed toxicities were concluded to be a direct result of the displacement. More recently, the role of binding displacement as a cause of clinically important drug interactions has been questioned (0' Arcy & McElnay 1982; McElnay & 0' Arcy 1983; Sellers 1979; Shand et at. 1975). With our present understanding of the influence of plasma protein binding on the distribution and elimination of drugs (Gillette 1973; MacKichan 1984; Shand et at. 1975; Yacobi et at. 1975), we now recognise that the adverse consequences of many interactions that were originally attributed to displacement were in fact caused by the effect of the displacers on the elimination of the displaced drugs. Protein binding displacement interactions are 'clinically important' if they require a temporary or sustained reduction in the daily dose of the displaced drug. This will occur if the displacement results in a temporary or sustained increase in the unbound drug concentration in plasma. The goals of this article are to describe the theoretical effects of displacement on unbound concentrations of drug in plasma, and to review examples of drug displacement interactions for which the mechanisms are known. It is concluded that although drug displacement is common and sometimes predictable, it alone is rarely responsible for observations of adverse drug interactions.