Protein binding - clinical relevance
Changes in the fraction of bound drug may potentially change the concentration at the target site. If the fraction of unbound drug increases, the amount of drug that can distribute to other tissues and induce a pharmacologic (or toxic) response could increase. However, two factors are of importance that have a compensatory effect on the increased unbound plasma concentration:
- Because the fraction of drug in the plasma is usually low (and most of the drug is located in tissue), an increase in unbound drug in the plasma will only result in a relatively small change in the amount of drug in the tissues. Particularly for drugs with a high Volume of distribution, a change in the fraction unbound drug in the plasma does hardly effect the concentration in the tissues (and at the target site). In example: when a drug has a Volume of distribution of 500 litres, and the plasma volume is 5 litres, then the percentage of drug in tissue is 99% (1- Vplasma / Vd). If the 1% of drug in the plasma shows an increase in fraction unbound, it still contributes to a minor extent to the 99% drug found in the tissue. Even in the extreme event when the fraction of unbound drug in the plasma will double, this increase won’t change the drug concentration in the tissues and thus at the target site. Note that in some cases with drugs will a low Volume of Distribution and a very small therapeutic window (e.g. warfarin), changes in protein binding occur that may lead to clinical consequences.
- When the fraction of unbound drug increases, the fraction that will be able to be eliminated (e.g. via hepatic or renal clearance) also increases (since elimination of bound drug is restricted). An increase in plasma concentration of unbound drug will therefore be 'compensated' by increased clearance.