The unbound drug is that fraction  of drug in plasma or tissues that is no bound to plasma or tissue proteins. A reversible equilibrium normally exists between the unbound drug and the protein bound drug. Only the unbound drug is considered to be pharmacologically active and in equilibrium with the receptor site. This fraction appears to be responsible for the dose-related therapeutic effects and adverse reaction. The unbound fraction is also available for excretion and elimination.

Certain drugs have a marked hepatic uptake that is capable of rapidly shifting the equilibrium from bound to unbound drug. This creates the effect of so called protein stripping by the liver. For these drugs increased protein binding results in enhanced hepatic clearance. Changes in their rate of metabolism depend mainly on hepatic blood flow. For other drugs an increase in unbound drug generally leads to increased hepatic metabolism. The rate of metabolism of such drugs is normally independend of liver blood flow. Protein binding limits glomerular filtration but generally does not influence renal tubular secretion, which also appears to strip bound drug.

The unbound fraction of some drugs, e.g., phenytoin, is dependent on the concentration of plasma proteins and may be altered in disease states that produce hypoalbuminemia. Throughout the therapeutic plasma concentration range, unbound drug is usually a constant fraction of total drug in plasma.

Interaction by displacement may temporarily increase the concentration of unbound drug. Redistribution and enhanced metabolism often modify this increase, but it may remain clinically relevant if the drug has a small volume of distribution. The interaction may be of little importance if the volume of distribution is very large.

Volume of distribution is that volume of fluid into which the drug appears to distribute with a concentration equal to that in plasma. It is a purely theoretical entity that gives an expression of the extent to which the drug passes from the plasma to peripheral tissues.