CACO-2 CELL-PERMEABILITY OF A NEW (HYDROXYBENZYL)ETHYLENEDIAMINE ORALIRON CHELATOR - CORRELATION WITH PHYSICOCHEMICAL PROPERTIES AND ORAL ACTIVITY

This study describes the transport of CGP 75254A, a novel oral iron ch elator, across Caco-2 cells in an attempt to model intestinal epitheli al cell permeability in man. CGP 75254A was dosed to the apical side o f Caco-2 cell monolayers, together with [C-14]mannitol as an internal permeability standard. The apparent permeability (P-app) was calculate d from the cumulative appearance of drug in the basolateral fluid with time. The [C-14]mannitol P-app indicated that the Caco-2 monolayers r emained intact and that the iron chelator was not toxic to the cells. Permeabilities of CGP 75254A were compared with the Caco-2 permeabilit ies of compounds of known absorption in man. The results predict that absorption of CGP 75254A is likely to be virtually complete at pH valu es between 5.5 and 7.0. However, at pH 8.0 permeability is predicted a s negligible. Cell permeability data are in full accordance with key p hysicochemical properties of CGP 75254A and suggest that the drug is p assively absorbed. The results, which suggest likely quantitative abso rption in vivo, are supported by preliminary pharmacological experimen ts in marmosets.