Abstract

Ultrafiltration was used to study the enantioselective binding of R-, S- and racemic flurbiprofen, an arylpropionic acid nonsteroidal anti-inflammatory drug, to human plasma protein in eight normal volunteers. The percent free of the R was greater than that of the S for most subjects, but the ratio of percent unbound R to S ranged from 0.52 to 1.33. In extensive studies with a single representative plasma, the percent unbound of the individual enantiomers was independent of concentration up to 26 micrograms/ml, although the binding of the S enantiomer (0.048 +/- 0.007%) was greater than that of the R (0.082 +/- 0.017%), whereas that of the racemate (0.065 +/- 0.028%) was intermediate. At supratherapeutic concentrations of the enantiomers, the percent free of both R- and S-flurbiprofen increased to 0.252 at 100 micrograms/ml. A one-site binding model with nonspecific binding described the data well for R-, S- and racemic flurbiprofen; resulting Ka values were 3.39 X 10(6), 7.31 X 10(6) and 4.35 X 10(6) M-1, respectively. The binding of each enantiomer in the presence of varying amounts of its antipode was described best by a simple competitive inhibition model where mutual displacement occurred as concentrations increased beyond 26 micrograms/ml. The binding of racemic flurbiprofen in elderly and obese volunteers and patients with liver disease was not significantly different from normal subjects, but binding was less in hypoalbuminemic patients and patients with renal impairment. Uremia decreased the binding of R-flurbiprofen preferentially.