Protein binding and clearance of oxaprozin, a highly bound anti-inflammatory agent

Abstract

Conventional dialysis cells were used in initial attempts to determine the binding characteristics of oxaprozin (4,5-diphenyl-2-oxazoleproplonic acid, Wy-21,743). Equilibration required dialysis times up to 22 hours at 37°C resulting in deterioration of plasma proteins, which in turn leads to highly variable binding values. In contrast, dialysis with Dianorm^™ cells requires less than 4 hours to reach equillibrium. The configuration of the cell optimizes the contact between the solutes and the membrane and allows for a more efficient mixing and exchanging of the solute. The percentage of unbound drug was linearly related to total drug in human plasma samples to which oxaprozin in clinically relevant concentrations (55–405 μg/ml) had been added. Likewise, a linear relationship between total drug concentration and the percentage unbound was observed in specimens from a pharmacokinetic study in healthy volunteers. Clearance of total oxaprozin from plasma correlated with the percentage unbound drug. Thus the higher clearance observed under steady-state conditions (where concentrations are higher than following single dose administration) was caused by a larger unbound fraction available to the elimination sites.