The Ethanol Metabolite Acetaldehyde Increases Paracellular Drug Permeability In Vitro and Oral Bioavailability In Vivo

Abstract

Alcohol consumption leads to the production of the highly reactive ethanol metabolite, acetaldehyde, which may affect intestinal tight junctions and increase paracellular permeability. We examined the effects of elevated acetaldehyde within the gastrointestinal tract on the permeability and bioavailability of hydrophilic markers and drug molecules of variable molecular weight and geometry. In vitro permeability was measured unidirectionally in Caco-2 and MDCKII cell models in the presence of acetaldehyde, ethanol, or disulfiram, an aldehyde dehydrogenase inhibitor, which causes acetaldehyde formation when coadministered with ethanol in vivo. Acetaldehyde significantly lowered transepithelial resistance in cell monolayers and increased permeability of the low-molecular-weight markers, mannitol and sucrose; however, permeability of high-molecular-weight markers, polyethylene glycol and inulin, was not affected. In vivo permeability was assessed in male SpragueDawley rats treated for 6 days with ethanol, disulfiram, or saline alone or in combination. Bioavailability of naproxen was not affected by any treatment, whereas that of paclitaxel was increased upon acetaldehyde exposure. Although disulfiram has been shown to inhibit multidrug resistance-1 P-glycoprotein (P-gp) in vitro, our data demonstrate that the known P-gp substrate paclitaxel is not affected by coadministration of disulfiram. In conclusion, we demonstrate that acetaldehyde significantly modulates tight junctions and paracellular permeability in vitro as well as the oral bioavailability of low-molecular-weight hydrophilic probes and therapeutic molecules in vivo even when these molecules are substrates for efflux transporters. These studies emphasize the significance of ethanol metabolism and drug interactions outside of the liver.

Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions

“…Both ethanol and acetaldehyde, the product of oxidative metabolism, induced a reduction of TER and increased permeability of mannitol, sucrose and inulin in intestinal epithelial cells [126]. In Caco-2 cells, acetaldehyde-increased barrier permeability was due to dissociation of E-cadherin, -catenin, occludin, and ZO-1 from cellular junctions, their redistribution from the membrane to an intracellular location and reorganization of actin cytoskeleton [127].…”

Effects of borneol on the intestinal transport and absorption of two P-glycoprotein substrates in rats

“…In terms of drugs themselves, poor bioavailability can be a result of low solubility (Brouwers et al, 2009), low permeability (Fisher et al, 2010) or high metabolism of drugs (Hurst et al, 2007). Formulation approaches have been developed to improve the oral bioavailability of drugs, such as modification of chemical structure and dosage forms (Sagara et al, 1996).…”

Acetaldehyde disrupts tight junctions in Caco-2 cell monolayers by a protein phosphatase 2A-dependent mechanism

“…A significant body of evidence shows that ethanol consumption induces intestinal epithelial barrier dysfunction and increased gut permeability, leading to endotoxemia in human subjects and experimental animals (27,28,31). In the intestinal epithelial cell monolayers in vitro, ethanol is less effective in disruption of tight junctions (10,30). On the other hand, acetaldehyde disrupts tight junctions and increases paracellular permeability in Caco-2 cell monolayers (30).…”