Research Articles
Prediction of Plasma Protein Binding Displacement and its Implications for Quantitative Assessment of Metabolic Drug–Drug Interactions from In Vitro Data

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Abstract

Although displacement from plasma protein binding (dPB) is usually of little clinical significance, it should be taken into account when interpreting changes in total plasma concentrations of drugs subject to metabolically based drug–drug interactions (mDDI). The aim of this study was to develop an approach to predict changes in the free fractions (fu) of pairs of drugs that compete for plasma binding, knowing their binding affinity constants, and to consider the implications of associated concentration- and time-dependence of such changes with respect to drug exposure. Experimental fu values of valproic acid and phenytoin in the presence of ibuprofen, diflunisal, or naproxen were predicted successfully (within 0.99- to 1.36-fold) by the model. In addition, the simulation of time-dependent changes in fu of valproic acid following administration of ibuprofen indicated different extents of dPB during ‘first-pass’ through the liver after oral absorption and on systemic recirculation. To understand the impact of the time-dependent change in fu, a full physiologically based pharmacokinetic model, that accounts for concentration-time profile of displacee and displacer and their mutual effect on each other, is required. The approach developed in this study is a first step towards the development of such a model.

Section snippets

INTRODUCTION

According to the free drug hypothesis, there are only a limited number of cases where displacement from plasma proteins (dPB) will cause significant changes in drug response.1 This is because the increase in free drug concentration is generally transient as a result of redistribution and increased clearance (fu will be higher and total plasma concentration lower, but free drug concentration returns to the original value, hence effect stays the same). It is well known that dPB causes problems in

THEORETICAL

In the two-binding site model, drug A (the displaced drug) is considered to bind to two independent sites on the protein, P1 (the primary site) and P2 (a secondary site). Drug B (the displacing drug) is assumed to displace drug A from the primary binding site only. Thus, the binding reactions are indicated as follows:A+P1KA1AP1A+P2KA2AP2B+P1KB1BP1The corresponding equilibrium association constants for drugs A and B are given by Equations (4., 5., 6.), where KA1, KA2, and KB1 refer to the

General Assessment of the Model

The effects of displacement predicted by the theoretical equations described above were assessed by simulating outcomes with eight virtual displacee drugs having different albumin binding characteristics. They were 95% bound in the absence of displacement at concentrations of 100 or 500 µM and were assigned appropriate association constants for the primary and secondary binding sites in order to span a range of association constant values. The latter values were different at the two

RESULTS

The effect of increasing displacer concentration on the fu value of the virtual displaced drugs at a total concentration of 100 µM is shown for one- and two-site models in Fig. 1A and numbers for the free fraction of the displacee (fu,A) and the displacer (fu,B) are given in Tab. 2. The increase in fu of the displacee is greatest when it binds only to one site. The displacer free fraction is greater than that expected in the absence of the displacee and so both compounds will exhibit higher

DISCUSSION

Equations were developed to predict the increase in free fractions of drugs competing for binding to HSA, assuming one- and two-site models, and, in the latter case assuming that the displacer drug binds only at the primary site. Their use depends on knowledge of the relevant association constants, the concentrations of the interacting drugs and the total albumin concentration. Simulations with virtual model drugs were carried out to investigate the properties of the equations, which were also

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