free drug fraction

Of all the drug circulating in plasma, only a portion is riding free and unattached; the rest is glued to proteins. The free drug fraction is that unbound slice — and it is the only part that can actually slip out of the blood, bind receptors and produce an effect. The bound part is, for the moment, just along for the ride.

Free fraction (often written fu) ranges from nearly all of the drug for weakly bound agents to a tiny percentage for highly bound ones. Because only free drug crosses membranes, it is the free concentration that equilibrates with the site of action and that the kidney filters and the liver metabolises. Bound and free are in constant equilibrium: remove free drug and bound drug releases to top it up.

The free fraction explains why total plasma levels can mislead. If protein binding falls (low albumin, displacement by another drug), total drug may look unchanged or even lower while the free, active fraction rises. For drugs with a narrow margin such as phenytoin or warfarin, this can shift the balance between benefit and harm.