Recent advances in techniques to determine free
drug concentrations have lead to a substantial increase in the monitoring of this parameter in clinical practice. The majority of
drug binding to macromolecules in serum can be accounted for by association with
albumin and
alpha 1-acid glycoprotein.
Albumin is the primary
binding protein for acidic drugs, while binding to
alpha 1-acid glycoprotein is more commonly observed with basic lipophilic agents. Alterations in the concentrations of either of these macromolecules can result in significant changes in free fraction. Diseases such as
cirrhosis,
nephrotic syndrome and
malnourishment can result in hypoalbuminaemia.
Burn injury,
cancer,
chronic pain syndrome,
myocardial infarction, inflammatory diseases and
trauma are all associated with elevations in the concentration of
alpha 1-acid glycoprotein. Treatment with a number of drugs has also been shown to increase
alpha 1-acid glycoprotein serum concentrations. A wide variety of
biological fluids have been examined for their ability to provide an estimation of free
drug concentration at receptor sites. The most useful fluid for estimating free
drug concentrations appears to be plasma or serum, with subsequent treatment of the sample to separate free and bound
drug by an appropriate technique. The two most widely used methods are equilibrium dialysis and ultrafiltration. Of these two, ultrafiltration has the greatest utility clinically because it is rapid and relatively simple. The major difficulty associated with this method involves the binding of
drug to the ultrafilters, but significant progress has been made in solving this problem. Several authors have endorsed the routine use of free
drug concentration monitoring. Data examining the clinical usefulness of free
drug concentration monitoring for
phenytoin,
carbamazepine,
valproic acid,
disopyramide and
lignocaine (
lidocaine) are reviewed. While available evidence suggests that free concentrations may correlate with clinical effects better than total
drug concentrations, there are insufficient data to justify the recommendation of the routine use of free
drug concentration monitoring for any of these agents at present.