Thomas P G, Seelig J
Institute of Molecular Biology and Medical Biotechnology, University of Utrecht, The Netherlands.
Biochem J. 1993 Apr 15;291 ( Pt 2)(Pt 2):397-402. doi: 10.1042/bj2910397.
We have examined the partitioning/transfer of the Ca2+ antagonist flunarizine from the aqueous phase into phospholipid bilayers. We show that the binding of the cationic amphiphilic drug flunarizine to phospholipid bilayers displays traditional linear concentration-dependent characteristics once unmasked of electrostatic effects. The coefficient for the binding/partitioning of flunarizine to phosphatidylcholine was found to be 28700 M-1, supporting the notion that this drug may be particularly membrane-active. The thermodynamics of the partitioning/transfer process have also been studied using high-sensitivity titration calorimetry. Binding was found to be predominantly enthalpy-driven with only a small entropic contribution; delta H = -22.1 kJ.mol-1 (-5.3 kcal.mol-1) at 27 degrees C. This is in conflict with established ideas of entropy-driven partitioning of drugs into phospholipid membranes as a result of the 'hydrophobic effect'. The strong enthalpic nature of binding is interpreted as being indicative of strong lipophilic interactions between the drug and the phospholipid phase.
我们研究了钙离子拮抗剂氟桂利嗪从水相到磷脂双层的分配/转移情况。我们发现，一旦消除静电效应，阳离子两亲性药物氟桂利嗪与磷脂双层的结合呈现出传统的线性浓度依赖性特征。氟桂利嗪与磷脂酰胆碱的结合/分配系数为28700 M-1，这支持了该药物可能具有特别强的膜活性这一观点。我们还使用高灵敏度滴定热分析法研究了分配/转移过程的热力学。结果发现结合主要由焓驱动，熵的贡献很小；在27℃时，ΔH = -22.1 kJ·mol-1（-5.3 kcal·mol-1）。这与因“疏水效应”导致药物熵驱动分配到磷脂膜中的既定观点相矛盾。结合的强焓性质被解释为表明药物与磷脂相之间存在强的亲脂相互作用。
