Tibell A, Lindholm A, Säwe J, Chen G, Norrlind B
Department of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
Pharmacol Toxicol. 1995 Feb;76(2):115-21. doi: 10.1111/j.1600-0773.1995.tb00115.x.
In the commercially available intravenous formulation of Cyclosporin A (Sandimmun), polyoxyethylated castor oil (Cremophor EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.
在市售的环孢素A静脉制剂（山地明）中，聚氧乙烯蓖麻油（聚氧乙烯氢化蓖麻油）用作增溶剂。我们最近报道，在大鼠模型中，用大豆油基脂肪乳剂替代聚氧乙烯氢化蓖麻油可减轻该制剂的急性肾毒性作用。为了进一步探索脂肪乳剂作为环孢素A载体的潜力，需要有关体内药代动力学和组织分布的数据。在这项猪的研究中，将大豆油 - 环孢素A的药代动力学与山地明的药代动力学进行了比较。两种制剂似乎具有生物等效性，因为在全身清除率、分布容积或消除半衰期方面没有显著差异。此外，在大鼠中比较了大豆油 - 环孢素A和山地明的组织分布。这些研究还包括另外两种基于脂质的载体：一种基于罂粟籽油的碘化酯，另一种基于脂质体制剂。无论使用何种载体，组织分布都相似。脂肪乳剂载体似乎为制备耐受性更好的环孢素A静脉制剂提供了可能性，同时在药代动力学和组织分布方面保持相同的特性。
