Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics
KS Saitta, C Zhang, KK Lee, K Fujimoto, MR Redinbo… - Xenobiotica, 2014 - Taylor & Francis
KS Saitta, C Zhang, KK Lee, K Fujimoto, MR Redinbo, UA Boelsterli
Xenobiotica, 2014•Taylor & FrancisWe 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 …
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 …
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.
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