Microcalorimetric study for the binding of ionic drugs to human erythrocytes and the ghost membranes.
The binding of phenothiazine derivatives (as cationic drugs) and non-steroidal anti-inflammatory drugs (as anionic drugs) to human erythrocytes and ghost membranes has been compared with respect to their thermodynamic characteristics, by flow microcalorimetry at pH 7.4 and 37 C. From enthalpyentropy correlation, it was shown that anionic and cationic drugs are bound to different binding sites on the membranes. Phenothiazines bind to a single common site of the erythrocyte membranes with relatively high binding affinities (K = 10(4)-10(5) M-1). The binding is entropy-driven and characterized by a small negative enthalpy (delta H) and a positive entropy change (delta S), reflecting hydrophobic interactions. However, the binding reaction for the intact erythrocytes shows large negative values for both delta H and delta S. The values of K for the membranes and delta H for the intact erythrocytes increased with the increase of the hydrophobic character of the substituent group at the C-2 position of the phenothiazine nucleus (H less than Cl less than CF3). The results indicate that phenothiazines bind and or penetrate to the inner membranes of the erythrocytes and react with intracellular components such as haemoglobin, while anti-inflammatory drugs bind to the surface protein on the membranes with a lower affinity (K = 10(3) M-1) than phenothiazines, reflecting the small negative delta H and positive delta S for the interaction with intact erythrocytes.
Aki
H
H
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Yamamoto
M
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood; D002151:Calorimetry; D004910:Erythrocyte Membrane / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010640:Phenothiazines / Q000097:blood; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004364:Pharmaceutical Preparations; D010640:Phenothiazines