Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics

Xenobiotica. 2014 Jan;44(1):28-35. doi: 10.3109/00498254.2013.811314. Epub 2013 Jul 5.


1. We have previously demonstrated that a small molecule inhibitor of bacterial β-glucuronidase (Inh-1; [1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]) protected mice against diclofenac (DCF)-induced enteropathy. Here we report that Inh-1 was equally protective against small intestinal injury induced by other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin (10 mg/kg, ip) and ketoprofen (100 mg/kg, ip). 2. Inh-1 provided complete protection if given prior to DCF (60 mg/kg, ip), and partial protection if administered 3-h post-DCF, suggesting that the temporal window of mucosal protection can be extended for drugs undergoing extensive enterohepatic circulation. 3. Pharmacokinetic analysis of Inh-1 revealed an absolute bioavailability (F) of 21% and a short t1/2 of <1 h. This low F was shown to be due to hepatic first-pass metabolism, as confirmed with the pan-CYP inhibitor, 1-aminobenzotriazole. 4. Using the fluorescent probe 5 (and 6)-carboxy-2',7'-dichlorofluorescein, we demonstrated that Inh-1 did not interfere with hepatobiliary export of glucuronides in gall bladder-cannulated mice. 5. These data are compatible with the hypothesis that pharmacological inhibition of bacterial β-glucuronidase-mediated cleavage of NSAID glucuronides in the small intestinal lumen can protect against NSAID-induced enteropathy caused by locally high concentrations of NSAID aglycones.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Chromatography, Liquid
  • Diclofenac / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Glucuronidase / antagonists & inhibitors*
  • Hepatocytes / drug effects
  • Indomethacin / adverse effects
  • Intestinal Diseases / chemically induced*
  • Intestinal Diseases / prevention & control*
  • Intestine, Small / pathology
  • Ketoprofen / adverse effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology*
  • Statistics, Nonparametric
  • Tandem Mass Spectrometry
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacokinetics
  • Thiourea / pharmacology


  • 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Quinolones
  • Diclofenac
  • Ketoprofen
  • Glucuronidase
  • Thiourea
  • Indomethacin