Wenk M R, Fahr A, Reszka R, Seelig J
Department of Biophysics, University of Basel, Switzerland.
J Pharm Sci. 1996 Feb;85(2):228-31. doi: 10.1021/js950120i.
Paclitaxel (taxol) is diterpenoid anticancer drug with a new mechanism of cytostatic action. It is under investigation in clinical trials for treatment of various types of human cancer. A major difficulty in developing paclitaxel as a chemotherapeutic agent in its poor water solubility. In order to improve the bioavailability of paclitaxel, novel vehicle systems such as mixed micelles or liposome-based formulations are being developed. In this study we determined the partition coefficient of paclitaxel partitioning into small unilamellar lipid vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine using two different methods, namely high-sensitivity titration calorimetry and fluorescence spectrometry. We measured a partition coefficient of Kp approximately equal to 9,500 M-1, a partition enthalpy of Delta H = -25 +/- 3 kcal mol-1 and a free energy of binding of Delta G = -7.9 kcal mol-1. The binding reaction is enthalpy-driven, which can be explained by van der Waals interactions between the hydrophobic drug and the strong temperature dependence of the partition equilibrium. A temperature increase of 10 degrees C reduces the paclitaxel solubility in the lipid phase by a factor of 4.
紫杉醇是一种具有全新细胞生长抑制作用机制的二萜类抗癌药物。目前正处于临床试验阶段，用于治疗各类人类癌症。紫杉醇作为一种化疗药物，其主要难点在于水溶性较差。为了提高紫杉醇的生物利用度，人们正在研发新型载体系统，如混合胶束或脂质体剂型。在本研究中，我们采用两种不同方法，即高灵敏度滴定热分析法和荧光光谱法，测定了紫杉醇在由1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱构成的小单层脂质囊泡中的分配系数。我们测得分配系数Kp约为9500 M-1，分配焓ΔH = -25 ± 3 kcal mol-1，结合自由能ΔG = -7.9 kcal mol-1。该结合反应是由焓驱动的，这可以通过疏水性药物之间的范德华相互作用以及分配平衡对温度的强烈依赖性来解释。温度升高10℃会使紫杉醇在脂质相中的溶解度降低4倍。
