Solid-supported lipid membranes as a tool for determination of membrane affinity: High-throughput screening of a physicochemical parameter

Abstract

Quantification of membrane affinity is an important early screening step in modern drug design. However, current approaches using different lipid membrane models usually are time-consuming or show severe experimental drawbacks. In this paper we describe the use of solid-supported lipid membranes (TRANSIL®) as a new tool for the determination of membrane affinity. Eighteen pharmaceuticals (neutrals, acids, and bases) have been analyzed for their lipophilicity at physiological pH in an automated setup; phase separation of lipid and aqueous phase can be achieved simply by a short low-speed centrifugation or filtration. The membrane affinity is then calculated by quantification of the total drug concentration and the amount of drug remaining in the aqueous phase after incubation with solid-supported lipid membranes. Lipophilicity parameters relying on solid-supported lipid membranes correlate well with octanol–water partition coefficients Kow for neutral organic compounds (range of log Kow = 1.5–5, n = 7, r = 0.93). Data acquisition with this lipid membrane model system is highly re-producible. Even in the case of ionizable drugs, where Kow tends to underestimate membrane affinity, the latter can be correctly quantified using solid-supported lipid membranes: data comparison shows good agreement of the presented approach with established but time-consuming standardized lipid/buffer systems. Solid-supported lipid membranes allow a fast and reliable quantification of membrane affinity, enabling high-throughput screening of this physicochemical parameter. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:599–606, 2001