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Protein Binding Displacement Interactions and their Clinical Importance

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Summary

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 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.

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  1. Department of Pharmacy, The Queen’s University of Belfast, Belfast Medical Biology Centre, 97 Lisburn Rd, Belfast, BT9 7BL, Northern Ireland

    J. C. McElnay & P. F. D’Arcy

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McElnay, J.C., D’Arcy, P.F. Protein Binding Displacement Interactions and their Clinical Importance. Drugs 25, 495–513 (1983). https://doi.org/10.2165/00003495-198325050-00003

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