title: Sucrose esters increase drug penetration, but do not inhibit p-glycoprotein in caco-2 intestinal epithelial cells.
abstract: Sucrose fatty acid esters are increasingly used as excipients in pharmaceutical products, but few data are available on their toxicity profile, mode of action, and efficacy on intestinal epithelial models. Three water-soluble sucrose esters, palmitate (P-1695), myristate (M-1695), laurate (D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40, were tested on Caco-2 cells. Caco-2 monolayers formed a good barrier as reflected by high transepithelial resistance and positive immunostaining for junctional proteins claudin-1, ZO-1, and β-catenin. Sucrose esters in nontoxic concentrations significantly reduced resistance and impedance, and increased permeability for atenolol, fluorescein, vinblastine, and rhodamine 123 in Caco-2 monolayers. No visible opening of the tight junctions was induced by sucrose esters assessed by immunohistochemistry and electron microscopy, but some alterations were seen in the structure of filamentous actin microfilaments. Sucrose esters fluidized the plasma membrane and enhanced the accumulation of efflux transporter ligands rhodamine 123 and calcein AM in epithelial cells, but did not inhibit the P-glycoprotein (P-gp)-mediated calcein AM accumulation in MES-SA/Dx5 cell line. These data indicate that in addition to their dissolution-increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes without inhibiting P-gp.
authors.affiliation: Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6726, Hungary; Department of Pharmaceutical Technology, University of Szeged, Szeged, H-6720, Hungary.
authors.forename: Lóránd
authors.initials: L
authors.lastname: Kiss
authors.forename: Éva
authors.initials: É
authors.lastname: Hellinger
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Pilbat
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Kittel
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Török
authors.forename: András
authors.initials: A
authors.lastname: Füredi
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
authors.forename: Szilvia
authors.initials: S
authors.lastname: Veszelka
authors.forename: Péter
authors.initials: P
authors.lastname: Sipos
authors.forename: Béla
authors.initials: B
authors.lastname: Ózsvári
authors.forename: László G
authors.initials: LG
authors.lastname: Puskás
authors.forename: Monika
authors.initials: M
authors.lastname: Vastag
authors.forename: Piroska
authors.initials: P
authors.lastname: Szabó-Révész
authors.forename: Mária A
authors.initials: MA
authors.lastname: Deli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000737:chemistry; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D013395:Sucrose / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004952:Esters; D013395:Sucrose
keywords: Caco-2 cells; P-glycoprotein; absorption enhancer; drug permeability; efflux pumps; epithelial; membrane fluidity; sucrose ester; tight junction; toxicity