Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics.
Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics.
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DOI：
10.3109/00498254.2013.811314
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Boelsterli UA
中科院分区：
文献类型：
--
作者：
Saitta KS;Zhang C;Lee KK;Fujimoto K;Redinbo MR;Boelsterli UA
我们之前已经证明，细菌葡萄糖醛酸酶(INH-1；[1-((6，8-dimethyl-2-oxo-1，2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]))的小分子抑制剂可以保护小鼠免受双氯芬酸(β)诱导的肠病的影响。在此，我们报道了InH-1对其他含有羧酸的非类固醇抗炎药(NSAIDs)、吲哚美辛(10 mg/kg，ip)和酮洛芬(100 mg/kg，ip)所致的小肠损伤具有同等的保护作用。在DCF前给予INH-1(60 mg/kg，ip)可提供完全保护，如果在DCF后3h给予INH-1则提供部分保护，这表明对于经历广泛肠-肝循环的药物，粘膜保护的时间窗口可以延长。药代动力学分析表明，INH-1的绝对生物利用度(F)为21%，短的t1/2为1h，这种低的生物利用度是肝脏首过代谢所致，这一结果被PAN-CYP抑制剂1-氨基苯并三氮唑所证实。用荧光探针5(和6)-羧基-2‘，7’-二氯荧光素，我们证明InH-1不干扰胆管插管小鼠肝胆管葡萄糖醛酸苷的输出。这些数据支持这样的假设，即药物抑制细菌β-葡萄糖醛酸酶介导的非甾体抗炎药葡萄糖醛酸苷在小肠腔中的裂解可以预防局部高浓度非甾体抗炎药苷元引起的非甾体抗炎药所致的肠病。
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). 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. 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. 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. 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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DOI：
10.1124/jpet.102.044107
发表时间：
2003-02-01
影响因子：
3.5
作者：
Zamek-Gliszczynski, MJ;Xiong, H;Brouwer, KLR
通讯作者：
Brouwer, KLR
DOI：
10.1126/science.1191175
发表时间：
2010-11-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wallace BD;Wang H;Lane KT;Scott JE;Orans J;Koo JS;Venkatesh M;Jobin C;Yeh LA;Mani S;Redinbo MR
通讯作者：
Redinbo MR
影响因子：
3.8
作者：
KRETZROMMEL, A;BOELSTERLI, UA
通讯作者：
BOELSTERLI, UA
影响因子：
3.7
作者：
Scarpignato, Carmelo;Hunt, Richard H.
通讯作者：
Hunt, Richard H.
影响因子：
3.8
作者：
Lim, Miao Shan;Lim, Priscilla L. K.;Boelsterli, Urs A.
通讯作者：
Boelsterli, Urs A.