title: Oral absorption enhancement of cromolyn sodium through noncovalent complexation.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Ding
authors.forename: Parshuram
authors.initials: P
authors.lastname: Rath
authors.forename: Robert
authors.initials: R
authors.lastname: Angelo
authors.forename: Thomas
authors.initials: T
authors.lastname: Stringfellow
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Flanders
authors.forename: Steven
authors.initials: S
authors.lastname: Dinh
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Orellana
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Robinson
mesh_terms: D000042:Absorption / Q000187:drug effects / Q000502:physiology; D000284:Administration, Oral; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D004205:Cromolyn Sodium / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D004357:Drug Synergism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D004205:Cromolyn Sodium