Thermodynamics of the Binding of Phenothiazines to Human Plasma, Human Serum Albumin and α1-Acid Glycoprotein: A Calorimetric Study

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Abstract
A flow microcalorimetric study has been carried out to investigate the interactions between phenothiazine derivatives and human plasma, human serum albumin (HSA) and α1acid glycoprotein (AGP) at pH 7·4 and 37°C. The direct analyses of enthalpic titration curves allowed the determination of the binding enthalpy change (δH), the apparent binding constant (K), and the number of the binding sites (n), as well as the evaluation of the apparent free energy (δG), and entropy (δS) changes. The overall binding of phenothiazines was exothermic with negative δH, which was compensated for by changes in δS. The values of δG were relatively insensitive to variation in the molecular details of the binding reaction. HSA possessed two classes of binding sites for phenothiazines. The first (n1 = 1), with high affinity (K1 = 105–106 M−1) was characterized by small negative δH and positive δS values due to hydrophobic interaction. The second class of sites had a low affinity (K2 = 103-104 M−1) and high capacity (n2 = 3–8) and contributed to the negative δH and δS values. The binding and thermodynamic parameters were influenced by the aliphatic side chain moieties on the phenothiazine nucleus. On the other hand, the drugs were bound to AGP at a single common binding site with a binding affinity of the order of 104M−1, characterized by negative δH and δS values, which partially reflected the effect of a van der Waals' interaction. In plasma the drugs were bound as a result of an enthalpy-driven type of reaction having large negative δH and a large binding capacity resulting from the presence of AGP and HSA.

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