Fisher SJ, Swaan PW, Eddington ND
The Ethanol Metabolite Acetaldehyde Increases Paracellular Drug Permeability In Vitro and Oral Bioavailability In Vivo. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Oct 9.
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 co-administered 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 Sprague-Dawley rats treated for six days with ethanol, disulfiram, or saline alone or in combination. Bioavailability of naproxen was not affected by any treatment, while that of paclitaxel was increased upon acetaldehyde exposure. While disulfiram has been shown to inhibit MDR1 P-glycoprotein in vitro, our data demonstrate that the known P-gp substrate paclitaxel is not affected by co- administration 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.
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