Multilamellar liposomes and solid-supported lipid membranes (TRANSIL):: Screening of lipid-water partitioning toward a high-throughput scale

被引:59
作者
Loidl-Stahlhofen, A
Hartmann, T
Schöttner, M
Röhring, C
Brodowsky, H
Schmitt, J
Keldenich, J
机构
[1] Nimbus Biotechnol GmbH, D-04317 Leipzig, Germany
[2] Bayer AG, Pharmaceut Res, D-42096 Wuppertal, Germany
关键词
lipid-water partitioning; membrane affinity; automation; liposomes; solid-supported lipid membranes; membrane composition; pH dependence;
D O I
10.1023/A:1013343117979
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Purpose. Lipid-water partitioning of 187 pharmaceuticals has been assessed with solid-supported lipid membranes (TRANSIL) in microwell plates and with multilamellar liposomes for a data comparison. The high-throughput potential of the new approach was evaluated. Methods. Drugs were incubated at pH 7.4 with egg yolk lecithin membranes either on a solid support (TRANSIL beads) or in the form of multilamellar liposomes. Phase separation of lipid and water phase was achieved by ultracentrifugation in case of liposomes or by a short filtration step in case of solid-supported lipid membranes. Results. Lipid-water partitioning data of both approaches correlate well without systematic deviations in the investigated lipophilicity range. The solid-supported lipid membrane approach provides high-precision data in an automated microwell-plate setup. The lipid composition of the solid-supported Lipid membranes was varied to study the influence of membrane change on lipid-water partitioning. In addition, pH-dependent measurements have been performed with minimal experimental effort. Conclusions. Solid-supported lipid membranes represent a valuable tool to determine physiologically relevant lipid-water partitioning data of pharmaceuticals in an automated setup and is well suited for high-throughput data generation in lead optimization programs.
引用
收藏
页码:1782 / 1788
页数:7
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