Thermodynamics of lipophilic drug binding to intestinal fatty acid binding protein and permeation across membranes

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Intestinal fatty acid binding protein (I-FABP) is present at high levels in the absorptive cells of the intestine (enterocytes), where it plays a role in the intracellular solubilization of fatty acids (FA). However, I-FABP has also been shown to bind to a range of non-FA ligands, including some lipophilic drug molecules. Thus, in addition to its central role in FA trafficking, I-FABP potentially serves as an important intracellular carrier of lipophilic drugs. In this study we provide a detailed thermodynamic analysis of the binding and stability properties of I-FABP in complex with a series of fibrate and fenamate drugs to provide an insight into the forces driving drug binding to I-FABP. Drug binding and selectivity for I-FABP are driven by the interplay of protein-ligand interactions and solvent processes. The Gibbs free energies (δG°) determined from dissociation constants at 25 °C ranged from-6.2 to-10 kcal/mol. The reaction energetics indicate that drug binding to I-FABP is an enthalpy-entropy driven process. The relationship between I-FABP stability and drug binding affinity was examined by pulse proteolysis. There is a strong coupling between drug binding and I-FABP stability. The effect of an I-FABP protein sink on the kinetics and thermodynamics of tolfenamic acid permeation across an artificial phospholipid membrane were investigated. I-FABP significantly decreased the energy barrier for desorption of tolfenamic acid from the membrane into the acceptor compartment. Taken together, these data suggest that the formation of stable drug-I-FABP complexes is thermodynamically viable under conditions simulating the reactant concentrations likely observed in vivo and maybe a significant biochemical process that serves as a driving force for passive intestinal absorption of lipophilic drugs.

Original languageEnglish
Pages (from-to)557-570
Number of pages14
JournalMolecular Pharmaceutics
Issue number2
Publication statusPublished - 6 Apr 2009


  • Drug absorption
  • Intestinal fatty acid binding protein
  • Intracellular drug transport
  • Lipophilic drug binding

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