Simultaneous use of sodium deoxycholate and dipotassium glycyrrhizinate enhances the cellular transport of poorly absorbed compounds across Caco-2 cell monolayers.
The absorption-enhancing effect of a combination of sodium deoxycholate and dipotassium glycyrrhizinate in Caco-2 cell monolayers has been compared with that of the enhancers when used alone, and the mechanism of the enhancement was partially elucidated. The effect of the combined compounds was evaluated by measurement of transepithelial electrical resistance (TEER) and the cellular permeability of the water-soluble model compounds sodium fluorescein (MW 376.3) and fluorescein isothiocyanate dextran (MW 4400). The TEER of the monolayers decreased with increasing concentrations of dipotassium glycyrrhizinate in combination with 0.02% (w/v) sodium deoxycholate for 20 min, and reached a minimum at 1% (w/v) dipotassium glycyrrhizinate. Although a combination of 0.02% (w/v) sodium deoxycholate and 1% (w/v) dipotassium glycyrrhizinate enhanced the cellular permeability of sodium fluorescein and fluorescein isothiocyanate dextran, 0.02% (w/v) sodium deoxycholate and 1% (w/v) dipotassium glycyrrhizinate alone had no effect on either the TEER of the monolayers or the cellular transport of the water-soluble compounds. Sequential and separate exposure of the monolayers to each enhancer for 10 min had no effect on the TEER, but a marked decrease in TEER was observed when both compounds were used in combination. The enhancing effect of the combination of sodium deoxycholate and dipotassium glycyrrhizinate was inhibited by H7, a protein kinase C (PKC) inhibitor, suggesting that dipotassium glycyrrhizinate might enhance the activation of PKC via sodium deoxycholate. The combined use of these two enhancers had no toxic effects. These results provide useful, basic information on the action of these absorption enhancers on drugs for which absorption is limited owing to polarity or molecular size, or both.
Sakai
M
M
Hisamitsu Pharmaceutical Co. Inc., Tsukuba Laboratories, Ibaraki, Japan.
Imai
T
T
Ohtake
H
H
Azuma
H
H
Otagiri
M
M
D000042:Absorption / Q000187:drug effects*; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D003911:Dextrans / Q000493:pharmacokinetics; D004357:Drug Synergism; D017097:Electric Impedance; D004817:Epidermis / Q000187:drug effects* / Q000502:physiology; D019793:Fluorescein / Q000493:pharmacokinetics; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D006801:Humans; D010539:Permeability / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012995:Solubility
D003902:Detergents; D003911:Dextrans; C015219:fluorescein isothiocyanate dextran; D003840:Deoxycholic Acid; D019695:Glycyrrhizic Acid; D011493:Protein Kinase C; D016650:Fluorescein-5-isothiocyanate; D019793:Fluorescein