Aki H, Yamamoto M
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
J Pharm Pharmacol. 1990 Sep;42(9):637-41. doi: 10.1111/j.2042-7158.1990.tb06622.x.
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.
通过在pH 7.4和37℃下的流动微量热法，比较了吩噻嗪衍生物（作为阳离子药物）和非甾体抗炎药（作为阴离子药物）与人红细胞和血影膜结合的热力学特征。从焓-熵相关性可知，阴离子和阳离子药物与膜上不同的结合位点结合。吩噻嗪以相对较高的结合亲和力（K = 10⁴ - 10⁵ M⁻¹）结合到红细胞膜的单一共同位点。这种结合是熵驱动的，其特征是焓变（ΔH）为小的负值，熵变（ΔS）为正值，反映了疏水相互作用。然而，完整红细胞的结合反应显示ΔH和ΔS均为大的负值。膜的K值和完整红细胞的ΔH值随着吩噻嗪核C-2位取代基疏水特性的增加而增加（H ＜ Cl ＜ CF₃）。结果表明，吩噻嗪结合和/或渗透到红细胞内膜并与细胞内成分如血红蛋白反应，而抗炎药以比吩噻嗪更低的亲和力（K = 10³ M⁻¹）结合到膜表面蛋白上，这反映了与完整红细胞相互作用时小的负ΔH和正ΔS。
