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J. Biol. Chem., Vol. 280, Issue 18, 17769-17776, May 6, 2005

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The Interaction of Lipophilic Drugs with Intestinal Fatty Acid-binding Protein^*

Tony Velkov, Sara Chuang, Jerome Wielens, Harry Sakellaris¶, William N. Charman||, Christopher J. H. Porter||, and Martin J. Scanlon**

From the Departments of Medicinal Chemistry, ^||Pharmaceutics, and ^¶Microbiology, Monash University, Parkville 3052, Victoria, Australia

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 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.

Received for publication, September 7, 2004 , and in revised form, February 15, 2005.

^* This work was supported in part by a grant from the Australian Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Monash Research Fund fellowship.

^** To whom correspondence should be addressed: Dept. of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia. Tel.: 61-3-99039540; Fax: 61-3-99039582; E-mail: Martin.Scanlon{at}vcp.monash.edu.au.

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