title: Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ze-Yu
authors.initials: ZY
authors.lastname: Zhong
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Bin-Bin
authors.initials: BB
authors.lastname: Sun
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qiu-Shi
authors.initials: QS
authors.lastname: Xie
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xian-Ge
authors.initials: XG
authors.lastname: Tang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhao-Li
authors.initials: ZL
authors.lastname: Ling
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Kai-Jing
authors.initials: KJ
authors.lastname: Zhao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: The First Affiliated Hospital, Anhui University of Chinese Medicine, Hefei 230031, China.
authors.forename: Lun-Zhu
authors.initials: LZ
authors.lastname: Xia
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002417:Cattle; D002939:Ciprofloxacin / Q000494:pharmacology*; D004008:Diclofenac / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004764:Enterohepatic Circulation / Q000187:drug effects*; D004926:Escherichia coli / Q000378:metabolism; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D007410:Intestinal Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D002939:Ciprofloxacin; D005966:Glucuronidase