Probing the action of permeation enhancers sodium cholate and n-dodecyl-β-d-maltoside in a porcine jejunal mucosal explant system

TY - JOUR

T1 - Probing the action of permeation enhancers sodium cholate and n-dodecyl-β-d-maltoside in a porcine jejunal mucosal explant system

AU - Michael Danielsen, E.

AU - Hansen, Gert H.

PY - 2018

Y1 - 2018

N2 - The small intestinal epithelium constitutes a major permeability barrier for the oral administration of therapeutic drugs with poor bioavailability, and permeation enhancers (PEs) are required to increase the paracellular and/or transcellular uptake of such drugs. Many PEs act as surfactants by perturbing cell membrane integrity and causing permeabilization by leakage or endocytosis. The aim of the present work was to study the action of sodium cholate (NaC) and N-dodecyl-β-D-maltoside (DDM), using a small intestinal mucosal explant system. At 2 mMboth NaC and DDM caused leakage into the enterocyte cytosol of the fluorescent probe Lucifer Yellow, but they also blocked the constitutive endocytotic pathway from the brush border. In additionan increased paracellular passage of 3-kDa Texas Red Dextran into the lamina propria was observedBy electron microscopy, both PEs disrupted the hexagonal organization of microvilli of the brush border and led to the apical extrusion of vesicle-like and amorphous cell debris to the lumenIn conclusion, NaC and DDM acted in a multimodal way to increase the permeability of the jejunal epithelium both by paracellular and transcellular mechanisms. However, endocytosis, commonly thought to be an uptake mechanism that may be stimulated by PEs, was not involved in the transcellular process.

AB - The small intestinal epithelium constitutes a major permeability barrier for the oral administration of therapeutic drugs with poor bioavailability, and permeation enhancers (PEs) are required to increase the paracellular and/or transcellular uptake of such drugs. Many PEs act as surfactants by perturbing cell membrane integrity and causing permeabilization by leakage or endocytosis. The aim of the present work was to study the action of sodium cholate (NaC) and N-dodecyl-β-D-maltoside (DDM), using a small intestinal mucosal explant system. At 2 mMboth NaC and DDM caused leakage into the enterocyte cytosol of the fluorescent probe Lucifer Yellow, but they also blocked the constitutive endocytotic pathway from the brush border. In additionan increased paracellular passage of 3-kDa Texas Red Dextran into the lamina propria was observedBy electron microscopy, both PEs disrupted the hexagonal organization of microvilli of the brush border and led to the apical extrusion of vesicle-like and amorphous cell debris to the lumenIn conclusion, NaC and DDM acted in a multimodal way to increase the permeability of the jejunal epithelium both by paracellular and transcellular mechanisms. However, endocytosis, commonly thought to be an uptake mechanism that may be stimulated by PEs, was not involved in the transcellular process.

KW - Brush border

KW - Enterocyte

KW - Intestinal permeation enhancers

KW - N-dodecyl-β-d-maltoside (ddm)

KW - Small intestine

KW - Sodium cholate (nac)

U2 - 10.3390/pharmaceutics10040172

DO - 10.3390/pharmaceutics10040172

M3 - Journal article

C2 - 30279382

AN - SCOPUS:85054788312

SN - 1999-4923

VL - 10

JO - Pharmaceutics

JF - Pharmaceutics

IS - 4

M1 - 172

ER -