Chromatographic indexes on immobilized artificial membranes for the prediction of transdermal transport of drugs

A set of 12 drugs, consisting of structurally unrelated neutral, basic, aci dic and amphoteric compounds, was examined by high performance liquid chrom atrography (HPLC) on a model of fluid membrane bilayers, the immobilized ar tificial membrane (IAM) column. The logarithms of chromatographic capacity factors extrapolated to 100% aqueous phase at pH 5.5 (log k(w)) were measur ed and compared to the n-octanol/water partition coefficients (log P). The scale derived from the IAM system was different from the lipophilicity scal e expressed by the log P, due to the peculiar capability of phospholipids t o well accommodate the ionized form of some molecules and show additive or repulsive extra-interactions when particular structural motifs on the molec ule are present. The relationship between log P and log k(w) previously obt ained for compounds interacting on IAM phase by a uniquely lipophilicity-ba sed mechanism, allowed us to calculate, from log P, the values of log k(w) expected for the drugs considered. These values were subtracted from the lo g k(w) experimentally determined and the differences were assumed to quanti fy the amount of extra-interactions (hydrogen bond and electrostatic intera ctions) with phospholipids (Delta log k(w)). The coefficients of permeabili ty through the human skin (K-p) for the compounds considered did not correl ate with either log k(w) or log P values. However, the K-p values correlate d well with the Delta log k(w) values indicating that the higher the abilit y of a molecule to cross the skin barrier, the lower its component of inter action with phospholipids not accounted for by lipophilicity-based interact ions. (C) 1998 Elsevier Science S.A. All rights reserved.