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

Velkov, Tony 2009, Thermodynamics of lipophilic drug binding to intestinal fatty acid binding protein and permeation across membranes, Molecular pharmaceutics, vol. 6, no. 2, pp. 557-570, doi: 10.1021/mp800227w.

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Title Thermodynamics of lipophilic drug binding to intestinal fatty acid binding protein and permeation across membranes
Author(s) Velkov, Tony
Journal name Molecular pharmaceutics
Volume number 6
Issue number 2
Start page 557
End page 570
Publisher American Chemical Society
Place of publication Washington, D.C.
Publication date 2009-04-06
ISSN 1543-8384
1543-8392
Keyword(s) Intestinal fatty acid binding protein
drug absorption
lipophilic drug binding
intracellular drug transport
Summary 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.
Language eng
DOI 10.1021/mp800227w
Field of Research 111504 Pharmaceutical Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2009, American Chemical Society
Persistent URL http://hdl.handle.net/10536/DRO/DU:30018667

Document type: Journal Article
Collection: School of Medicine
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Created: Fri, 11 Sep 2009, 09:22:35 EST by Rachael Wilson

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