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Nonionic Surfactants Increase Digoxin Absorption in Caco-2 and MDCKII MDR1 Cells: Impact on P-glycoprotein Inhibition, Barrier Function, and Repeated Cellular Exposure

Nonionic Surfactants Increase Digoxin Absorption in Caco-2 and MDCKII MDR1 Cells: Impact on P-glycoprotein Inhibition, Barrier Function, and Repeated Cellular Exposure

Ahmed A Abdulhussein Al-Ali, Bente Steffansen, René Holm, Carsten Uhd Nielsen

Int J Pharm. 2018 Nov 15;551(1-2):270-280.

PMID: 30240828

Abstract:

Nonionic surfactants commonly used in pharmaceutical formulations may have P-glycoprotein (P-gp) inhibiting and/or permeation enhancing effects. The present work aims to distinguish these effects and assess the degree of cellular recovery after multiple exposures to nonionic surfactants. The investigated surfactants were polysorbates (PS): PS20, PS40, PS60, PS65, PS80 and PS85; monosaccharide-based: lauroyl methyl glucamide and n-nonyl-β-D-glucopyranoside; or disaccharide-based: lauryl-β-D-maltoside and trehalose 6-laurate. Bi-directional permeability studies of digoxin and mannitol, and calcein-AM efflux assay were performed in cell cultures. Cellular recovery was evaluated by continuous measurements of transepithelial electrical resistance (TEER) in Caco-2 cell monolayers. Polysorbates with one fatty acid chain decreased the efflux of digoxin through P-gp inhibition in MDCKII MDR1 cells. Mono- and di-saccharide-based surfactants, in a dose dependent manner, enhanced digoxin absorptive permeability without decreasing the secretory permeability in Caco-2 cells, suggesting that the surfactants had a transcellular permeation enhancing effect. Caco-2 cell monolayers recovered to different degrees of 60-100% of the initial TEER values. Calcein-AM assay was found to be non-predictive to surfactants influence on digoxin permeability across cell monolayers. In conclusion, these results may assist, in a mechanism-based, selection of suitable surfactants for formulating oral dosage forms to enhance the absorption of low bioavailable P-gp substrates.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AS2121315	Nonionic Surfactants			Price

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