Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. II. 2-Phenylpropionic acid protein binding.

The binding of 2-phenylpropionic acid (2PPA) enantiomers to rabbit albumin has been studied using fatty-acid-free albumin, with and without oleic acid, and using plasma from control rabbits and from rabbits rendered uremic with uranyl nitrate. The models of binding examined included specific binding at one and at two species of binding site, nonspecific binding and with inhibition between enantiomers with competitive or noncompetitive kinetics. Although any one aspect of the data is adequately modeled by nonspecific binding together with a single species of specific site, the simplest physical model consistent with the whole data requires two species of specific site together with nonspecific binding. Oleic acid in vitro, or other modifiers in vivo, inhibit the binding at both specific sites and reduce nonspecific binding. The inhibition at one site is sufficient that the situation in whole plasma simplifies to one site plus nonspecific binding. Competition between enantiomers occurs at this remaining site, at which R-2PPA binds more avidly than S-2PPA. Both specific and non-specific binding are reduced further in uranyl nitrate-induced renal failure. In the light of these findings, we discuss the implications of enantioselective binding and of competition between enantiomers for binding sites on the interpretation of drug disposition studies.