Background

Apart from the intravenous route, where a drug is introduced directly into the blood stream, all other routes of administration, where the site of action is remote from the site of administration, involve the absorption of the drug into the blood. Once the drug reaches the blood it partitions between the plasma and the red blood cells, the erythrocytes. Drug in plasma partitions between the plasma proteins (mainly albumin) and the plasma water. It is the free or unbound drug in plasma water, and not the drug bound to the proteins, that passes out of the plasma through the capillary endothelium and to tissues and hence the site(s) of action.

A dynamic equilibrium exists between the concentration of the drug in the blood plasma and the drug at its site(s) of action. This is what is termed distribution, the degree of which will depend largely on the physicochemical properties of the drug, in particular its lipophilicity. As it is frequently difficult to access the drug at its site(s) of action, its concentration in the plasma is often taken as a surrogate for the concentration at its site(s) of action. Even though the unbound drug in the plasma would give a better estimate of the concentration of the drug at its site(s) of action, this requires much more complex and sensitive assays than a measurement of the total concentration of the drug (i.e. the sum of the bound and unbound drug) within the blood plasma. Thus it is this total drug concentration within the plasma that is usually measured for clinical purposes. Therefore, plasma protein binding is a critical parameter to consider when investigating the therapeutic effect of a drug molecule.

The concentration of the drug in blood plasma depends on numerous factors. These include the amount of an administered dose that is absorbed and reaches the systemic circulation; the extent of distribution