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Interaction between Penicillins and Human Serum Albumin: A Thermodynamic Study of Micellar-like Clusters on a Protein

1999; American Chemical Society; Volume: 16; Issue: 3 Linguagem: Inglês

10.1021/la990538m

1520-5827

Pablo Taboada, Vı́ctor Mosquera, Juan M. Ruso, Félix Sarmiento, Malcolm N. Jones,

Drug Transport and Resistance Mechanisms

The thermodynamic parameters for the interaction of a range of penicillins, nafcillin, cloxacillin, dicloxacillin, and flucloxacillin, with human serum albumin (HSA) in aqueous solution, pH 7.4, 25 °C, have been determined using a combination of equilibrium dialysis and microcalorimetric techniques. The drugs bind largely nonspecifically to HSA to various extents ranging from ∼1200 (dicloxacillin) to ∼3000 (nafcillin) drug molecules per HSA molecule as the free drug concentration approaches the critical concentration (cc) for aggregation of the free drug. Maxima in the binding isotherms are found for nafcillin and cloxacillin, which possibly relate to maxima in monomeric drug activity in the vicinity of the critical concentrations (ccs). In the case of the dicloxacillin−HSA system, the binding isotherm reflects the two ccs observed for dicloxacillin corresponding to aggregate formation and the sphere-to-rod aggregate transition. The enthalpies of binding are small and exothermic so that the Gibbs energies of binding are dominated by large increases in entropy consistent with hydrophobic interactions. The magnitudes of the thermodynamic parameters for the interactions are similar to these for the interactions of anionic surfactants with globular proteins. The results are consistent with the clustering of drug molecules to the protein to form micellar-like structures.