It has become increasingly clear that not only the stomach but also the small intestine is a major target of nonsteroidal anti-inflammatory drug (NSAID)-associated toxicity. The acyl glucuronide metabolites of the NSAIDs are cleaved by intestinal bacterial β-d-glucuronidase, releasing the ulcerogenic aglycone. LoGuidice et al. evaluated the protective effects of a bacteria-selective β-d-glucuronidase inhibitor, Inhibitor-1 (Inh-1), against the enteric toxicity induced by diclofenac (DCF). Administration of an ulcerogenic dose of DCF (60 mg/kg i.p.) caused the formation of numerous large ulcers in the distal parts of the small intestine and increased intestinal permeability to fluorescein isothiocyanate-dextran, and pretreatment with Inh-1 (10 μg/mouse, b.i.d.) significantly alleviated mucosal injury and reduced all parameters of enteropathy. Pharmacokinetic profiling of DCF plasma levels revealed that Inh-1 coadministration did not significantly alter the Cmax, T1/2, or the area under the plasma concentration-versus-time curve of DCF. These studies demonstrate that pharmacologic targeting of luminal β-d-glucuronidase with a small-molecule inhibitor of the bacterial enzyme protects the gastrointestinal tract against DCF-induced enteropathy. Because this inhibitor is highly specific for bacterial β-d-glucuronidase and does not affect mammalian β-d-glucuronidases or kill bacteria or mammalian cells, this approach is novel and could have potential clinical implications.
See article at J Pharmacol Exp Ther 2012, 341:447–454.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics