Protein Binding Displacement Interactions and their Clinical Importance

Abstract

The binding of drugs to proteins is an important pharmacokinetic parameter. Many methods are available for the study of drug protein binding phenomena and there are also many ways to interpret the binding data. Although much emphasis has been placed on the binding of drugs in the plasma, binding also takes place in the tissues. Displacement interactions involving plasma or tissue binding sites have been implicated as the causative mechanisms in many drug interactions. However, the importance of plasma binding displacement as a mechanism of drug interactions. However, the importance of plasma binding displacement as a mechanism of drug interaction has been overestimated and overstated, being based largely on in vitro data. Because displaced drug can normally distribute out of the plasma compartment, increases of free drug concentrations are usually transient and therefore will not give rise to changed pharmacological effects in the patient. Those clinically important drug interactions formerly considered to be caused via displacement from plasma binding sites usually have another interaction mechanism involved; commonly decreased metabolism or renal elimination also takes place. Plasma binding displacement interactions, however, do become important clinically in certain specific situations, namely, when the displacing drug is administered quickly to the patient by the intravenous route, during therapeutic drug monitoring, and in certain drug disposition studies which involve the use of a heparin lock for blood sampling. Tissue binding displacement interactions have a greater potential to cause adverse effects in the patient as in this case drug will be forced from extravascular sites back into the plasma. The resulting increased drug plasma levels will lead to enhanced pharmacological effects and, possibly, frank toxicity. Displacement of drugs from binding sites simultaneously in both the plasma and in the tissues will combine the effects seen after displacement from the separate areas. Due to decreased binding in both areas, the free drug concentration in the plasma will increase leading to overactivity of the displaced drug.

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

“…An interaction Correspondence: PD Dr T. W. Guentert,Grenzacherstrasse, Basel, Switzerland with the binding of drugs, concomitantly present in blood, with a high affinity for this serum protein may therefore occur. Because unbound rather than total drug concentration in blood is generally believed to determine the intensity of pharmacologic effects, protein binding interactions are of clinical interest and have received much attention (for recent reviews see McElnay &D'Arcy, 1983 andReidenberg &Drayer, 1984). Accordingly, the unbound fractions of model compounds and representative drugs known to have a high affinity for serum albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and/or other binding proteins (ai-acid glycoprotein: prazosin, propranolol, quinidine, disopyramide; transcortin: prednisolone) were determined in the absence and presence, respectively, of two concentrations of placebo mixed micelles of the Valium-MM®-type formulation.…”

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

“…These have come from pharmacokinetic theory [6][7][8][9][10][11] and from the demonstration of other mechanisms for observed interactions (see Table 1). …”

Protein Binding of Phenytoin and Lidocaine in Pediatric Patients with Type I Diabetes Mellitus

“…At thera peutic total serum concentrations of phenytoin (0.8 X 10-4-1.2 X 10~4 M) in pa tients with normal serum pH and total albumin concentrations (6.0 X 10-4 M), the binding of phenytoin is not concentration dependent [7,8,41], In the serum samples obtained from our clinically stable patients, the temperature and pH were controlled dur ing analysis to obviate their potential effects on phenytoin binding. As a consequence, the free fraction of phenytoin in all our samples (8.33 ± 1.0%; table I) was well within the reported therapeutic range for free serum phenytoin [26-28, 39, 41].…”

“…Garlick and Mazer [3] have further demonstrated that lysine-525 is the predominant site of nonenzymatic glycation of human serum albumin in vivo. Several reviews concerning protein glycation in DM [4,5], the effects of disease states on plasma protein binding of drugs [6,7] and pharmacokinetic consequences of altered plasma protein binding [8,9] make no men tion of altered drug protein binding conse quent to DM. It should be noted, however, that Shaklai et al [10] have demonstrated that the binding affinities of bilirubin and cis-parinaric acid for glycated albumin were markedly reduced (50% for bilirubin and approximately 20-fold for cis-parinaric acid) when compared to nonglycated albumin.…”