The interaction of lipophilic drugs with intestinal fatty acid-binding protein

Velkov, Tony, Chuang, Sara, Wielens, Jerome, Sakellaris, H, Charman, William N., Porter, Christopher J. H. and Scanlon, Martin J. 2005, The interaction of lipophilic drugs with intestinal fatty acid-binding protein, Journal of biological chemistry, vol. 280, no. 18, pp. 17769-17776, doi: 10.1074/jbc.M410193200.

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Title The interaction of lipophilic drugs with intestinal fatty acid-binding protein
Author(s) Velkov, Tony
Chuang, Sara
Wielens, Jerome
Sakellaris, H
Charman, William N.
Porter, Christopher J. H.
Scanlon, Martin J.
Journal name Journal of biological chemistry
Volume number 280
Issue number 18
Start page 17769
End page 17776
Publisher American Society of Biological Chemists
Place of publication Baltimore, Md.
Publication date 2005-05-06
ISSN 0021-9258
Summary Intestinal fatty acid-binding protein (I-FABP) is a small protein that binds long-chain dietary fatty acids in the cytosol of the columnar absorptive epithelial cells (enterocytes) of the intestine. The binding cavity of I-FABP is much larger than is necessary to bind a fatty acid molecule, which suggests that the protein may be able to bind other hydrophobic and amphipathic ligands such as lipophilic drugs. Herein we describe the binding of three structurally diverse lipophilic drugs, bezafibrate, ibuprofen (both R- and S-isomers) and nitrazepam to I-FABP. The rank order of affinity for I-FABP determined for these compounds was found to be R-ibuprofen {approx} bezafibrate > S-ibuprofen >> nitrazepam. The binding affinities were not directly related to aqueous solubility or partition coefficient of the compounds; however, the freely water-soluble drug diltiazem showed no affinity for I-FABP. Drug-I-FABP interaction interfaces were defined by analysis of chemical shift perturbations in NMR spectra, which revealed that the drugs bound within the central fatty acid binding cavity. Each drug participated in a different set of interactions within the cavity; however, a number of common contacts were observed with residues also involved in fatty acid binding. These data suggest that the binding of non-fatty acid lipophilic drugs to I-FABP may increase the cytosolic solubility of these compounds and thereby facilitate drug transport from the intestinal lumen across the enterocyte to sites of distribution and metabolism.
Language eng
DOI 10.1074/jbc.M410193200
Field of Research 030401 Biologically Active Molecules
110104 Medical Biochemistry: Lipids
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, The American Society for Biochemistry and Molecular Biology
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Document type: Journal Article
Collection: School of Medicine
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