ABSORPTION ENHANCEMENT IN INTESTINAL EPITHELIAL CACO-2 MONOLAYERS BY SODIUM CAPRATE - ASSESSMENT OF MOLECULAR-WEIGHT DEPENDENCE AND DEMONSTRATION OF TRANSPORT ROUTES

Sodium caprate (C10), a medium chain fatty acid, is used clinically to enhance rectal absorption of the low molecular weight (MW) drug ampic illin. The main aim of this study was to investigate whether C10 also enhances the permeability of high MW model drugs in a model of the int estinal epithelium. The second aim was to present visual evidence of t he route of enhanced transport across the epithelial cell layer. The s tudies were performed in Caco-2 monolayers cultured on permeable suppo rts. The effects of non-toxic concentrations (less than or equal to 13 mM) of C10 on drug transport across the monolayers was studied using monodisperse C-14-polyethylene glycols (MW 238-502; C-14-PEGs), I-125- Arg(8)-vasopressin (MW 1,208), I-125-insulin (MW 6,000) and FITC-label led dextrans (MW 4,400 and 19,600; FD4 and FD20 respectively) as model drugs. Electron and confocal laser scanning microscopy were used to d emonstrate transport routes across the epithelium. 10 mM C10 increased the permeability of all C-14-PEGs to approximately the same extent. 1 3 mM C10 increased the permeability of I-125-Arg(8)-vasopressin 10-fol d. Only small increases in FD4 and FD20 permeabilities were observed. After C10 exposure, both tight junctions with normal morphology and th ose with dilatations showed an increased permeability to ruthenium red , indicating that C10 enhanced the paracellular transport of molecules with a MW<1,000. Confocal microscopy showed that C10 increased the tr ansport of FD4 and FD20 by the paracellular route. In conclusion, nont oxic concentrations of C10 can be used to enhance the permeability of drugs of MW up to approximately 1,200. Enhancement of the absorption o f molecules larger than 4,000 is quantitatively insignificant. The enh anced permeability occurred via the paracellular pathway.