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Displacement of free fatty acids from albumin by chlorophenoxyisobutyrate.

A two-phase hexane-aqueous salts buffer, pH 7.45, has been used as a model system to study the displacement of strongly bound long-chain free fatty acids (FFA) from bovine serum albumin by a more weakly binding drug, chlorophenoxyisobutyrate, that is insoluble in the organic phase. The hydrophobic phase serves to trap unbound FFA, thereby reducing the bound ligand concentration, but does not solvate the more hydrophilic drug. At equilibrium chlorophenoxyisobutyrate displaces [ 14 C]FFA from albumin, in the order stearate > palmitate > myristate. A drug to albumin molar ratio of 2.2 reduces the binding of [ 14 C]palmitate to albumin by only 2%, but increases the organic concentration by 50%. The binding curve of [ 14 C]palmitate-albumin is shifted to the right by 1 mM chlorophenoxyisobutyrate, indicating competitive displacement. At a constant ratio of total drug to bound FFA, a greater fraction of FFA is displaced from albumin at higher FFA to albumin ratios, suggesting that FFA bound to lower-affinity sites are removed more readily. Thus, in a two-phase system, a ligand which binds weakly to albumin can competitively displace a tightly bound ligand that partitions favorably in the hydrophobic phase. The model may have general applications in explaining the mechanism of action of albumin-bound drugs that reduce circulating FFA levels.