Plasma protein binding displacement interactions--why are they still regarded as clinically important?

Throughout the history of science and medicine, apparently plausible hypotheses have been put forward to explain observations which are subsequently found to be incorrect. However, it may take much longer to remove incorrect but attractive hypotheses from textbooks and current opinion than to establish them in the first place. One such false doctrine is related to the clinical relevance of plasma protein binding displacement interactions. Despite the theoretical and experimental data to the contrary, the concept that plasma protein binding displacement is a common cause of clinically significant interactions may still be widely taught in some medical schools, often appears in textbooks and is accepted by many in the medical community and by drug regulators. The purpose of this article is to review the likely clinical importance of plasma protein binding displacement interactions and to suggest an algorithm for investigating potential interactions. I also wish to encourage teachers of therapeutics and drug regulators to regard protein binding displacement with the minor degree of attention it deserves. About 25-30 years ago, marked increases in prothrombin times were observed in patients who were taking phenylbutazone in addition to warfarin [1, 2]. Soon after, severe hypoglycaemia was described in patients taking sulphonamides in addition to tolbutamide [3]. In both cases the drug of interest is highly bound to plasma proteins, and in both cases it was correctly observed that the interacting drug displaced the drug of interest from plasma proteins and increased the free fraction in plasma. Although some authors suggested that other mechanisms might be responsible [2, 3], others attributed the cause of the altered drug response to plasma protein displacement [4, 5]. Other examples of clinically significant drug interactions which have been attributed to plasma protein binding displacement are presented in Table 1. Since the initial attribution of the interactions in Table 1 to plasma protein binding displacement, there have been two major reasons why many authors have doubted whether this attribution adequately explains the observed interactions. These have come from pharmacokinetic theory [6-11] and from the demonstration of other mechanisms for observed interactions (see Table 1). The pharmacokinetic argument is as follows: imagine our drug of interest, drug A, is given chronically to steady-state. Then drug B, which increases the free fraction of A, is added, As it is the free concentration of A which is responsible for its effects, will not the effect ofA be significantly increased? Acutely, the amount of drug A displaced will not only be available to interact with its receptor, but is also available to be distributed throughout the rest of the body. The extent of increase in the free concentration of A will be buffered by redistribution, with the increase being greatest for drugs with the smallest initial distribution volumes. As distribution of drug from plasma to its receptor is often not instantaneous but is characterised by a first-order process with comparable rate to general drug distribution, this will also reduce the extent of increase in the effect of A. However, any increase in freeA following redistribution will also be available for drug elimination. For low clearance (restrictively cleared) drugs, where intrinsic clearance of free drug is the only determinant of mean