3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.1.3 Protein binding
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Written by Resident Doctor Committee · Published
Binding proteins
Protein | Binds | Examples |
|---|---|---|
Albumin | Acidic and neutral drugs | Valproate, phenytoin, diazepam |
Alpha-1-acid glycoprotein | Basic lipophilic drugs | Most antipsychotics, tricyclics |
Binding is reversible, and bound drug dissociates quickly to replace free drug.
The unbound fraction is the unbound concentration divided by the total: a drug 90% bound has an unbound fraction of 0.10.
Only unbound drug crosses membranes such as the blood-brain barrier, reaches receptors and produces a response.
Binding of individual drugs
Drug | Plasma protein binding |
|---|---|
Diazepam | About 98 to 99%, mainly to albumin |
Sertraline | About 98% |
Fluoxetine, paroxetine | Above 90% |
Citalopram, fluvoxamine | About 77 to 80% |
Escitalopram | About 56%, the lowest SSRI |
Duloxetine and most other antidepressants | 85 to 98% |
Venlafaxine | About 27% |
Desvenlafaxine, venlafaxine's metabolite | About 30% |
Lithium | Unbound |
Desmethyldiazepam (nordazepam) is the main active metabolite of diazepam.
Volume of distribution
Plasma binding and tissue binding move the apparent volume of distribution (Vd) in opposite directions.
Bound drug is held in the circulation, so less plasma binding lets more drug reach the tissues and raises Vd.
Tissue binding can dominate: fluoxetine distributes widely despite high plasma binding.
Displacement and low albumin
Displacement interactions matter clinically only when binding capacity is reduced, as in renal disease with proteinuria and hypoalbuminaemia, when the unbound fraction of a highly bound drug rises.
Otherwise the displaced drug is distributed and eliminated faster, so free exposure at steady state changes little.
In hypoalbuminaemia the total level falls without a matching fall in active drug, so raising valproate to correct a low total level can cause toxicity.