环丙沙星阻断了双氯芬酸的肠肝循环，并部分通过抑制肠道β-葡萄糖醛酸酶活性减轻了大鼠非甾体抗炎药诱导的肠病。
Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity.
作者信息
Zhong Ze-Yu, Sun Bin-Bin, Shu Nan, Xie Qiu-Shi, Tang Xian-Ge, Ling Zhao-Li, Wang Fan, Zhao Kai-Jing, Xu Ping, Zhang Mian, Li Ying, Chen Yang, Liu Li, Xia Lun-Zhu, Liu Xiao-Dong
机构信息
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
The First Affiliated Hospital, Anhui University of Chinese Medicine, Hefei 230031, China.
出版信息
Acta Pharmacol Sin. 2016 Jul;37(7):1002-12. doi: 10.1038/aps.2016.54. Epub 2016 May 16.
AIM
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which may cause serious intestinal adverse reactions (enteropathy). In this study we investigated whether co-administration of ciprofloxacin affected the pharmacokinetics of diclofenac and diclofenac-induced enteropathy in rats.
METHODS
The pharmacokinetics of diclofenac was assessed in rats after receiving diclofenac (10 mg/kg, ig, or 5 mg/kg, iv), with or without ciprofloxacin (20 mg/kg, ig) co-administered. After receiving 6 oral doses or 15 intravenous doses of diclofenac, the rats were sacrificed, and small intestine was removed to examine diclofenac-induced enteropathy. β-Glucuronidase activity in intestinal content, bovine liver and E coli was evaluated.
RESULTS
Following oral or intravenous administration, the pharmacokinetic profile of diclofenac displayed typical enterohepatic circulation, and co-administration of ciprofloxacin abolished the enterohepatic circulation, resulted in significant reduction in the plasma content of diclofenac. In control rats, β-glucuronidase activity in small intestinal content was region-dependent: proximal intestine<distal intestine<ileal valve. Administration of ciprofloxac caused significant reduction of β-glucuronidase activity in distal small intestine, and particularly in ileal valve. Furthermore, ciprofloxacin (10-2000 μmol/L) dose-dependently inhibited β-glucuronidase activity in distal small intestine content or E coli incubated in vitro, but did not affect that in proximal small intestine content or bovine liver incubated in vitro. After receiving 6 oral doses or 15 intravenous doses of diclofenac, typical enteropathy was developed with severe enteropathy occurred in distal small intestine. Co-administration of ciprofloxacin significantly alleviated diclofenac-induced enteropathy.
CONCLUSION
Co-administration of ciprofloxacin attenuated enterohepatic circulation of diclofenac and alleviated diclofenac-induced enteropathy in rats, partly via the inhibition of intestinal β-glucuronidase activity.
目的
双氯芬酸是一种非甾体抗炎药（NSAID），可能会引起严重的肠道不良反应（肠病）。在本研究中，我们调查了环丙沙星的联合使用是否会影响双氯芬酸的药代动力学以及双氯芬酸诱导的大鼠肠病。
方法
在大鼠接受双氯芬酸（10mg/kg，灌胃，或5mg/kg，静脉注射）后评估双氯芬酸的药代动力学，同时联合或不联合环丙沙星（20mg/kg，灌胃）。在接受6次口服剂量或15次静脉剂量的双氯芬酸后，处死大鼠，取出小肠检查双氯芬酸诱导的肠病。评估肠内容物、牛肝和大肠杆菌中的β-葡萄糖醛酸酶活性。
结果
口服或静脉给药后，双氯芬酸的药代动力学特征显示出典型的肠肝循环，环丙沙星的联合使用消除了肠肝循环，导致双氯芬酸血浆含量显著降低。在对照大鼠中，小肠内容物中的β-葡萄糖醛酸酶活性具有区域依赖性：近端小肠<远端小肠<回盲瓣。环丙沙星的给药导致远端小肠，特别是回盲瓣中的β-葡萄糖醛酸酶活性显著降低。此外，环丙沙星（10-2000μmol/L）剂量依赖性地抑制远端小肠内容物或体外培养的大肠杆菌中的β-葡萄糖醛酸酶活性，但不影响近端小肠内容物或体外培养的牛肝中的β-葡萄糖醛酸酶活性。在接受6次口服剂量或15次静脉剂量的双氯芬酸后，出现典型的肠病，远端小肠发生严重肠病。环丙沙星的联合使用显著减轻了双氯芬酸诱导的肠病。
结论
环丙沙星的联合使用减弱了双氯芬酸的肠肝循环，并减轻了双氯芬酸诱导的大鼠肠病，部分原因是通过抑制肠道β-葡萄糖醛酸酶活性。
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