title: Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy , Storrs, Connecticut , USA and.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Saitta
authors.forename: Carmen
authors.initials: C
authors.lastname: Zhang
authors.forename: Kang Kwang
authors.initials: KK
authors.lastname: Lee
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Redinbo
authors.forename: Urs A
authors.initials: UA
authors.lastname: Boelsterli
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002853:Chromatography, Liquid; D004008:Diclofenac / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000187:drug effects; D007213:Indomethacin / Q000009:adverse effects; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D007421:Intestine, Small / Q000473:pathology; D007660:Ketoprofen / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D053719:Tandem Mass Spectrometry; D013890:Thiourea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000593369:1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D015363:Quinolones; D004008:Diclofenac; D007660:Ketoprofen; D005966:Glucuronidase; D013890:Thiourea; D007213:Indomethacin