Effect of total drug concentration on the free fraction in uremic sera

The effect of total drug concentration on the free fraction was studied in vitro using sera of uremic and nonuremic subjects. Both therapeutic and toxic concentrations of radiolabeled phenytoin, diazepam, and propranolol were used. The free fraction was separated by a pressure ultrafiltration method at 37 degrees C and determined from 200-microliters aliquots of serum and the ultrafiltrate. Sera from 11 acutely uremic and 10 chronically uremic patients and from 10 healthy control subjects were used. Only slight increases in the free fraction were found over the concentration range studied in both nonuremic and uremic subjects. The concentration-dependent increases in the unbound fraction of phenytoin and diazepam were quite negligible compared with the two- to threefold increases caused by uremia itself. Thus, variation in total concentrations of phenytoin, diazepam, and propranolol does not change the free fractions to a clinically significant degree even in uremic patients with a compromised binding capacity.