Research ArticlesPrediction of Plasma Protein Binding Displacement and its Implications for Quantitative Assessment of Metabolic Drug–Drug Interactions from In Vitro Data
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:The 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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Management of epilepsia in older
2018, Presse MedicalePharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats
2013, Journal of EthnopharmacologyCitation Excerpt :It showed that the inhibition of baicalin on CYP1A2 in vivo was weaker than its in vitro effect. Because the increase in unbound drug by a displacer will increase its hepatic clearance that, in turn, may mask a concomitant effect of the displacer as an enzyme inhibitor in decreasing drug clearance (Christensen et al., 2006), the effect of baicalin on protein binding of theophylline was analyzed. Our results showed that baicalin could increase the unbound theophylline (%).
Plasma protein binding: From discovery to development
2013, Journal of Pharmaceutical SciencesCitation Excerpt :Although HSA has eight binding sites, capable of binding to endogenous compounds as well as xenobiotics with varying affinities, two major sites of HSA are primarily involved in binding ligands and show a bias toward binding acidic drugs. The two HSA-sites are sometimes also referred to as warfarin-azapropazone site, Sudlow site I, and indole-benzodiazepine site, Sudlow site II.3 Despite its large size, HSA is not limited to plasma but is distributed extravascularly, as is AAG.
Human serum albumin: From bench to bedside
2012, Molecular Aspects of MedicineCitation Excerpt :Clinically important drug–drug interactions formerly considered to be caused via displacement from plasma protein binding sites usually have another interaction mechanism involved, like altered metabolism or changes in renal excretion. However, pharmacokinetic interactions due to displacement from plasma proteins become clinically important in specific situations: (i) for drugs highly bound to plasma proteins that have low clearance, narrow therapeutic index and small Vd, like warfarin, phenytoin, and tolbutamide (Rolan, 1994; Christensen et al., 2006), and (ii) when a displacing drug is co-administered to the patient via rapid intravenous injection (D’Arcy and McElnay, 1982; Rolan, 1994). As a consequence, the concentration of the primary drug in the plasma will quickly rise reaching receptors or entering a compartment into which it would usually reach lower concentrations.
On the influence of protein binding on pharmacological activity of drugs
2010, Journal of Pharmaceutical SciencesCitation Excerpt :It is assumed further that the contribution of possible drug elimination by the targeted tissue to the total body clearance is negligible. Drug protein binding depends on the concentration of plasma proteins, which can be altered due to various diseases, or, not that often, due to possible protein binding displacement by another drug (competitive protein binding),4 or due to relatively high drug concentration.5 It was publicized (based on the application of well‐stirred model) that for the most common case of the orally administered drugs subjected mainly to hepatic elimination, that AUCu is independent of protein binding.6
Consideration of the linear concentration increase of the unbound drug fraction in plasma
2009, Journal of Pharmaceutical Sciences