SODIUM LAURYL SULFATE INCREASES TILUDRONATE PARACELLULAR TRANSPORT USING HUMAN EPITHELIAL CACO-2 MONOLAYERS

The potential effect of the common pharmaceutical wetting agent, sodium lauryl sulphate (SLS), on the transport of the hydrophilic bisphosphonate, tiludronate, was investigated both by performing physico-chemical determinations of the SLS-tiludronate interaction and by measuring the paracellular transport of tiludronate (Boulenc et al., Biochem. Pharmacol., 46 (1993) 1591-1600) across the in vitro human intestinal epithelium model, i.e., Caco-2. SLS did not affect the contact angles determined with different liquids (glycerin, dioxane, sulphuric acid, water, mercury, heptane and decane) on tiludronate tablets. SLS influenced neither the disintegration of tiludronate tablets nor tiludronate solubility. However, both the efficiency and effectiveness of SLS, in reducing surface tension, were affected by tiludronate. Hence, the presence of 0.48 g/l tiludronate in a water solution changed the efficiency of SLS in reducing the surface tension from 1 to 0.3 g/l. Before evaluating tiludronate transport across Caco-2 monolayers, the reversible (absorption enhancement of orally administered drugs) and irreversible (cell cytotoxicity) effects of SLS on the viability of Caco-2 monolayers were investigated. Following a 1 h exposure of well-differentiated Caco-2 cells to SLS concentrations above 100 mg/l, mitochondrial dehydrogenase activity decreased in a concentration-dependent manner, cytosolic lactate dehydrogenase leakage occurred, mannitol transport was irreversibly increased and a structural separation of the tight junctions was observed by electron microscopy. SLS concentrations up to 80 mg/l did not affect mitochondrial dehydrogenase and cytosolic lactate dehydrogenase activities, while both a reversible increase in mannitol paracellular transport and tight junction opening were observed. Under these incubation conditions, tiludronate paracellular transport was increased in a concentration-dependent manner. These studies demonstrate that SLS increased tiludronate paracellular transport through its specific and transient effect on the permeability of the intercellular space.