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.
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.
Authors: Natalie L Trevaskis; Chun Min Lo; Li Yun Ma; Patrick Tso; Helen R Irving; Christopher J H Porter; William N Charman Journal: Pharm Res Date: 2006-08 Impact factor: 4.200
Authors: Trudy D Woudstra; Laurie A Drozdowski; Gary E Wild; M T Clandinin; Luis B Agellon; Alan B R Thomson Journal: Lipids Date: 2004-07 Impact factor: 1.880
Authors: H Poirier; I Niot; M C Monnot; O Braissant; C Meunier-Durmort; P Costet; T Pineau; W Wahli; T M Willson; P Besnard Journal: Biochem J Date: 2001-04-15 Impact factor: 3.857
Authors: Daniel Y Hung; Frank J Burczynski; Ping Chang; Andrew Lewis; Paul P Masci; Gerhard A Siebert; Yuri G Anissimov; Michael S Roberts Journal: Am J Physiol Gastrointest Liver Physiol Date: 2002-11-20 Impact factor: 4.052
Authors: Friedhelm Schroeder; Anca D Petrescu; Huan Huang; Barbara P Atshaves; Avery L McIntosh; Gregory G Martin; Heather A Hostetler; Aude Vespa; Danilo Landrock; Kerstin K Landrock; H Ross Payne; Ann B Kier Journal: Lipids Date: 2007-09-19 Impact factor: 1.880
Authors: Gordon S Lee; Katharina Kappler; Christopher J H Porter; Martin J Scanlon; Joseph A Nicolazzo Journal: Pharm Res Date: 2015-08-07 Impact factor: 4.200