INTESTINAL SAFETY OF WATER-SOLUBLE BETA-CYCLODEXTRINS IN PEDIATRIC ORAL SOLUTIONS OF SPIRONOLACTONE - EFFECTS ON HUMAN INTESTINAL EPITHELIAL CACO-2 CELLS

Effects of water-soluble beta-cyclodextrins (beta CDs) on intestinal e pithelial integrity were investigated, to establish the safe use of th ese beta CDs as solubilizers of spironolactone in paediatric enteral s olutions. Mannitol permeability and transepithelial resistance (TER) o f human intestinal epithelial Caco-2 cell monolayers during exposure t o dimethyl-beta-cyclodextrin (DM beta CD), hydroxypropyl-beta-cyclodex trin (HP beta CD) and sulphobutyl ether beta-cyclodextrin (SBE beta CD ) were followed. Staining methods were used to discern cells with dama ged membranes and to study the integrity of cytoskeletal actin and tig ht junctions. Cytotoxicity of the beta CDs was tested by effects on in tracellular dehydrogenase activity. Exposure to HP beta CD and SBE bet a CD solutions had only minor effects on the integrity of Caco-2 cell monolayers. In contrast, DM beta CD clearly increased the epithelial p ermeability for the hydrophilic marker [C-14]mannitol across Caco-2 mo nolayers, decreased TER and showed a dose-dependent cytotoxicity. Acco rding to staining, DM beta CD increased the permeability of the apical cell membrane without discernable effects on cytoskeletal actin. HP b eta CD and SBE beta CD appear to be safe additives for use in enteral spironolactone preparations with respect to their acute local effects on epithelial integrity.