title: Acid-base cosolvent method for determining aqueous permeability of amiodarone, itraconazole, tamoxifen, terfenadine and other very insoluble molecules.
abstract: 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, log P(o)(COS), measured in cosolvent solution, are converted to values expected under cosolvent-free conditions, using an in silico model based on Abraham H-bond acidity (alpha) and basicity (beta) descriptors, developed with the Algorithm Builder computer program, to obtain aqueous intrinsic permeability values: log P(o)=0.738+0.885 log P(o)(COS)-1.262alpha+0.436beta, r(2)=0.97, q(2)=0.96, s=0.38, n=32, F=279. Five sparingly-soluble weak bases (solubility <1 microg/ml), which could not be characterized without cosolvent, had their aqueous intrinsic permeability, P(o), estimated: miconazole 0.32 cm/s; itraconazole 3.2 cm/s; amiodarone 13 cm/s; tamoxifen 28 cm/s; terfenadine 162 cm/s.
authors.affiliation: pION Inc., Woburn, MA 01801, USA.
authors.forename: Jeffrey Alan
authors.initials: JA
authors.lastname: Ruell
authors.forename: Oksana
authors.initials: O
authors.lastname: Tsinman
authors.forename: Alex
authors.initials: A
authors.lastname: Avdeef
mesh_terms: D000143:Acids / Q000737:chemistry; D000638:Amiodarone / Q000737:chemistry / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D017964:Itraconazole / Q000737:chemistry / Q000493:pharmacokinetics*; D010539:Permeability / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D012997:Solvents / Q000737:chemistry; D013629:Tamoxifen / Q000737:chemistry / Q000493:pharmacokinetics*; D016593:Terfenadine / Q000737:chemistry / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry
chemical_list: D000143:Acids; D012997:Solvents; D014867:Water; D013629:Tamoxifen; D017964:Itraconazole; D016593:Terfenadine; D000638:Amiodarone