Modulation of Paracellular-like Drug Transport across an Artificial Biomimetic Barrier by Osmotic Stress-Induced Liposome Shrinking

Various types of artificial biomimetic barriers are widely utilized as in vitro tools to predict the passive transcellular transport of drug compounds. The current study investigated if the sandwich barrier PermeaPad(R), which is composed of tightly packed phospholipid vesicles enclosed between two support sheets, contributes to a transport mechanism that is paracellular-like, representing one of the alternative pathways of passive transport in vivo, primarily of relevance for hydrophilic drug compounds. To this end, we pretreated the commercial PermeaPad(R) barrier with NaCl solutions of either high or low osmolality prior to permeation experiments on reversed Franz cell setups with hydrophilic model compounds calcein and acyclovir and hydrophobic model compounds hydrocortisone and celecoxib. Our starting hypothesis was that the liposomes formed in the barrier during the hydration step should either shrink or swell upon contact with test media (drug solutions) due to osmotic pressure difference as compared to the pretreatment solutions. Apparent permeabilities for calcein and acyclovir across the PermeaPad(R) barrier were found to increase approximately 2.0 and 1.7 fold, respectively, upon hypo-osmotic pretreatment (soaking in hypotonic medium, while the permeation of hydrocortisone and celecoxib remained unchanged. A control experiment with lipid-free barriers (support sheets) indicated that the permeation of all the compounds was virtually unchanged upon hypo-osmotic pretreatment. In conclusion, soaking PermeaPad(R) in a medium of lower osmotic pressure than that used during the permeation study appears to induce the osmotic shrinking of the lipid vesicles in the barrier, leaving wider water channels between the vesicles and, thus, allowing hydrophilic compounds to pass the barrier in a paracellular-like manner.

Automated summary

Treating the PermeaPad(R) barrier with low osmolality solutions appears to enhance the transport of hydrophilic compounds by inducing the osmotic shrinking of lipid vesicles, creating wider water channels for compound passage.