Purpose: To determine the effect of Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) on the permeation of cromolyn across Caco-2 cell monolayers and explore the molecular basis for the enhanced absorption.
Methods: Transport studies of cromolyn across Caco-2 cell monolayers were conducted in the presence of various SNAC concentrations. Permeation of cellular transport markers and lactate dehydrogenase (LDH) release were measured to evaluate cell integrity. Molecular interactions betweent the two compounds were investigated using isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR), and Fourier-transfrom infrared (FTIR) spectroscopies and molecular dynamics simulations.
Results: The absorption of cromolyn across Caco-2 monolayers was enhanced markedly by SNAC. SNAC did not cause significant LDH leakage and changes in the permeation of transport markers. ITC, spectroscopies, and molecular dynamic simulations indicated the existence of intermolecular interactions between cromolyn and SNAC that involve the 2-hydroxybenzamide moiety on SNAC and weaken the hydrogen bonding between cromolyn and surrounding water molecules.
Conclusions: SNAC increases the permeability of Caco-2 monolayers to cromolyn without measurable cell damage. SNAC interacts with cromolyn mainly via ring stacking. One major mode of interaction appears to involve the insertion of the aromatic ring of SNAC between cromolyn's rings. Such interaction appears to reduce the hydration of cromolyn and thus optimize its hydrophobicity for oral absorption.