CHROMATOGRAPHIC INDEXES DETERMINED ON AN IMMOBILIZED ARTIFICIAL MEMBRANE (IAM) COLUMN AS DESCRIPTORS OF LIPOPHILIC AND POLAR INTERACTIONS OF 4-PHENYLDIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS WITH BIOMEMBRANES

A set of nine 4-phenyldihydropyridine (DHP) calcium-channel blockers i ncluding both ionizable and unionizable molecules has been examined. T he chromatographic parameters log k' have been determined by HPLC on a n immobilized artificial membrane (IAM) column which is a solid-phase model of fluid membranes. The influence of different percentages of or ganic modifier and ionic strength of the eluent on the chromatographic behaviour has been studied in order to identify the best experimental conditions modelling the in vivo interaction with phospholipids. As d ifferent ranking orders can occur under different experimental conditi ons, log k' values extrapolated to 100% aqueous phase (log k(w)(IAM)) have been determined. Moreover, n-octanol/buffer partition data at pH 7.4 and 12.5 (log D-7.4 and log P) and chromatographic data on a hydro carbon HPLC stationary phase (log k(w)(ODS)) have been measured. Compa rative studies between the experimental data, obtained for the differe nt systems, have shown that the IAM-derived scale is distinct from the one obtained by 'conventional' lipophilic indices, because of the par ticular behaviour of the basic DHPs. Moreover, only IAM parameters are good descriptors of the strong interactions of the basic DHPs with bi omembranes. In fact, the chromatography of neutral compounds is mainly lipophilicity dependent while a 'dual' mechanism, partition and ion-e xchange, operates for basic analogues. In this case the lipophilic com ponent is insensitive to the protonation of the basic function. Finall y receptor binding values from rat cortical brain preparations success fully correlate with log k(w)(IAM). Hence, the biomembrane affinity of DHPs appears to be a critical factor for access to their receptor sit e.