Fahr A, Holz M, Fricker G
Drug Delivery Systems, Sandoz Pharma AG, Basel, Switzerland.
Pharm Res. 1995 Aug;12(8):1189-98. doi: 10.1023/a:1016220211925.
Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics.
A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood.
Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood.
These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.
超过30篇出版物描述了环孢素A（CyA）的脂质体制剂，以替代聚氧乙烯蓖麻油（CrEL，一种乙氧基化甘油的三蓖麻醇酸酯）作为药物载体。然而，相互矛盾的报告使得无法就脂质体对CyA药代动力学（PK）和药效学的影响得出一致结论。
在大鼠中比较了一系列脂质体CyA制剂，这些制剂的脂质体组成和脂质剂量不同，但CyA剂量恒定。使用PK模型分析数据，该模型考虑了随着血液中脂质浓度变化而变化的分布容积。
脂质体的表面性质和脂质类型不是脂质体CyA重要的PK预测指标，至少对于小剂量脂质体而言如此。相反，环孢菌素的绝对脂质量和亲脂性是影响脂质体CyA PK的关键因素。血液中脂质浓度越高，环孢菌素的亲脂性越大，血液中CyA的浓度就越高。
这些关系可能解释了文献结果的不一致性。与我们小组早期的观察结果一起，上述发现表明，CyA并非被包裹在脂质体膜中。文献中关于肥胖大鼠与瘦大鼠相比CyA清除率较低和分布容积较小的报告支持了我们对所涉及机制的假设。提出了一个CyA分布的半定量模型，该模型指出血浆中CyA的可变游离分数是脂质体CyA制剂中所有先前报道现象的关键因素。
