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Fatty Acid Binding Proteins: Potential Chaperones of Cytosolic Drug Transport in the Enterocyte?

Pharmaceutical Research volume 28, pages 2176–2190 (2011)Cite this article

ABSTRACT

Purpose

Several poorly water-soluble drugs have previously been shown to bind to intestinal (I-FABP) and liver fatty acid binding protein (L-FABP) in vitro. The purpose of this study was to examine the potential role of drug binding to FABPs on intestinal permeability and gut wall metabolism in vivo.

Methods

The intestinal permeability of ibuprofen, progesterone and midazolam (which bind FABPs) and propranolol (which does not) was examined using an autoperfused recirculating permeability model in control rats and rats where FABP levels were upregulated via pre-feeding a fat-rich diet.

Results

The intestinal permeability of drugs which bind FABPs in vitro was increased in animals where FABP levels were upregulated by prefeeding a high fat diet. The gut wall metabolism of midazolam was also reduced in animals with elevated FABP levels.

Conclusions

Consistent with their role in the cellular transport of endogenous lipophilic substrates, FABPs appear to facilitate the intracellular disposition of drug molecules that bind FABPs in vitro. Drug binding to FABPs in the enterocyte may also attenuate gut wall metabolism in a manner analogous to the reduction in hepatic extraction mediated by drug binding to plasma proteins in the systemic circulation.

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Abbreviations

FABPs:

fatty acid binding proteins

I-FABP:

intestinal FABP

iLBP:

intracellular lipid binding proteins

L-FABP:

liver FABP

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ACKNOWLEDGMENTS

We would like to thank Dr. Sara Chuang and Dr. Tony Velkov for performing the experiments to measure the FABP binding affinity of the model drugs.

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Affiliations

  1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, Australia, 3052

    Natalie L. Trevaskis, Gary Nguyen & Christopher J. H. Porter

  2. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, Australia, 3052

    Martin J. Scanlon

Authors
  1. Natalie L. Trevaskis
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  2. Gary Nguyen
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  3. Martin J. Scanlon
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  4. Christopher J. H. Porter
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Correspondence to Christopher J. H. Porter.

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Trevaskis, N.L., Nguyen, G., Scanlon, M.J. et al. Fatty Acid Binding Proteins: Potential Chaperones of Cytosolic Drug Transport in the Enterocyte?. Pharm Res 28, 2176–2190 (2011). https://doi.org/10.1007/s11095-011-0446-1

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KEY WORDS

  • drug absorption
  • drug metabolism
  • fatty acid binding protein
  • intestinal permeability
  • poorly water-soluble drugs