Free Drug Concentration Monitoring in Clinical Practice

Abstract

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.

On-Capillary Sample Preconcentration Incorporated in Chiral Capillary Electrophoresis

“…Protein binding significantly affects the drug disposition, pharmacological activity and/or side effect.21, 22 The protein binding of a chiral drug is potentially stereoselective because of the inherent chirality of the plasma proteins.23,24 This is why the binding of a chiral drug should be investigated stereoselectively. The present CE system was applied to the stereoselective determination of unbound VER concentrations in human plasma.…”

“…' 8,19 In blood, a drug is usually bound to serum proteins, such as albumin and al-acid glycoprotein. Protein binding significantly affects the disposition, pharmacological activity and/or adverse effect of drug.21, 22 The extent of protein binding depends on the nature of the drug. Generally, a hydrophobic drug is strongly bound (ca.…”

Influence of intralipid on free propofol fraction assayed in human serum albumin solutions and human plasma

“…Moreover, the procedure of total drug assay is cheaper, quicker and simpler. Free drug measurement is recommended mainly for the potentially dangerous drugs of a narrow therapeutic window with significant toxic effects at higher concentrations and when the protein level is changing [2] , for example, in the case of renal or hepatic failure [3,4] . It should also be remembered that changes in the free fraction of a drug are more pronounced for highly-bound drugs, where even a slight decrease in protein binding may substantially increase their free fraction and cause a dangerous toxic effect.…”

Study of competitive binding of enantiomers to protein by affinity capillary electrochromatography

“…Most drugs undergo some degree of reversible binding to plasma proteins, a process which may have significant effects on the overall activity profile of the compounds [1,2]. High-performance affinity chromatography and zonal elution are typically used to probe the drug -protein interactions [3][4][5][6][7].…”