Partition coefficients of beta-blockers in bile salt/lecithin micelles as a tool to assess the role of mixed micelles in gastrointestinal absorption

The objective of this study was to develop non-invasive spectroscopic metho ds to quantify the partition coefficients of two beta -blockers, atenolol a nd nadolol, in aqueous solutions of bile salt micelles and to assess the ef fect of lecithin on the partition coefficients of amphiphilic drugs in mixe d bile salt/lecithin micelles, which were used as a simple model for the na turally occurring mixed micelles in the gastrointestinal tract. The partiti on coefficients (K-p) at 25.0 +/- 0.1 degreesC and at 0.1 M NaCl ionic stre ngth were determined by spectrofluorimetry and by derivative spectrophotome try, by fitting equations that relate molar extinction coefficients and rel ative fluorescence intensities to the partition constant K-p. Drug partitio n was controlled by the: (i) drug properties, with the more soluble drug in water (atenolol) exhibiting smaller values of K-p, and with both drugs int eracting more extensively in the protonated form; and by (ii) the bile salt monomers, with the dihydroxylic salts producing larger values of K-p for t he beta -blockers, and with glycine conjugation of the bile acid increasing the values of K-p for the beta -blockers. Addition of lecithin to bile sal t micelles decreases the values of K-p of the beta -blockers. Mixed micelle s incorporate hydrophobic compounds due to their large size and the fluidit y of their core, but amphiphilic drugs, for which the interactions are pred ominantly polar/electrostatic, are poorly incorporated in mixed micelles of bile salts/lecithin. (C) 2001 Elsevier Science B.V. All rights reserved.