Acid-Base Cosolvent Method for Determining Aqueous Permeability of Amiodarone, Itraconazole, Tamoxifen, Terfenadine and Other Very Insoluble Molecules

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A high-throughput, UV-detection PAMPA (parallel artificial membrane permeability assay) cosolvent procedure is described, based on the use of 20% v/v acetonitrile in aqueous buffer. A training set of 32 drugs (17 bases, 13 acids, 2 ampholytes) was studied both in aqueous buffer and in cosolvent-buffer solutions. A procedure was devised, where intrinsic permeability values, logP^<COS>_0, measured in cosolvent solution, are converted to values expected under cosolvent-free conditions, using an in silico model based on Abraham H-bond acidity (α) and basicity (β) descriptors, developed with the Algorithm Builder computer program, to obtain aqueous intrinsic permeability values : logP_0=0.738+0.885 logP^<COS>_0-1.262α+ 0.436β,r^2=0.97, q^2=0.96, s=0.38, n=32, F=279. Five sparingly-soluble weak bases (solubility <1μg/ml), which could not be characterized without cosolvent, had their aqueous intrinsic permeability, P_0, estimated : miconazole 0.32cm/s ; itraconazole 3.2cm/s ; amiodarone 13cm/s ; tamoxifen 28cm/s ; terfenadine 162cm/s.
2004-05-01