Advances in screening for membrane permeability: high-resolution PAMPA for medicinal chemists

The majority of orally administered drugs are described to be passively transported across the lipophilic cell membranes [Lennernäs, H. et al. (1994) Intestinal drug absorption during induced net water absorption in human; a mechanistic study using antipyrine, atenolol and enalaprilat. Br. J. Clin. Pharmacol. 37, 589-596; [1] Artursson, P. Application of physicochemical properties of molecules to predict intestinal permeability. Proceedings of the AAPS Workshop on Permeability Definitions and Regulatory Standards, Arlington, VA, 17-19 August 1998] [2]. Parallel artificial membrane permeability assay (PAMPA), as a passive-permeability screen with focus on the simulation of transcellular processes, is an excellent compliment to cellular models in absorption, distribution, metabolism, excretion (ADME) screening of research compounds. Being fast, versatile, and low-cost, PAMPA is a compelling and biologically relevant model of transport. The problem of low solubility of research compounds has been largely eliminated in the PAMPA method. This review will emphasize how high-resolution PAMPA can help in the design of structural features into molecules to improve their absorption-related properties.: