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Clinical significance of drug binding, protein binding, and binding displacement drug interactions.

Drugs widely used in clinical psychopharmacology, with few exceptions, are hepatically eliminated and circulate in the blood bound to plasma proteins. Often, the degree of binding is high (>90%). This fact has led to a widespread belief that such drugs may frequently participate in drug-binding interactions. The logic is as follows: Coadministration of drugs can result in a highly bound drug displacing a less avidly bound drug from its binding sites. This leads to greater amounts of free, nonprotein-bound, drug available for distribution to the sites of action. As free drug is a major determinant of pharmacologic effects, these drug interactions could result in toxicity and/or enhanced efficacy. This reasoning simplifies a complex situation where compensatory changes occur in the body to buffer the impact of drug-binding interactions. There are few examples where the above events have been documented to occur with psychoactive drugs leading to substantial clinical consequences. Although protein-binding displacement interactions are generally of minimal clinical significance, this is an assumption not based on evidence, but rather the lack of it. The purpose of this review is to examine some relevant aspects of drug-protein binding and draw conclusions for clinical practice about the significance of drug binding and drug-binding displacement interactions. Psychopharmacology Bulletin.