title: Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats.
abstract: OBJECTIVE
  Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs.
  
  
  METHODS
  Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a "cocktail" of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively.
  
  
  RESULTS
  Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results.
  
  
  CONCLUSIONS
  Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ming-xing
authors.initials: MX
authors.lastname: Miao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ze-yu
authors.initials: ZY
authors.lastname: Zhong
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004347:Drug Interactions; D024841:Fluoroquinolones / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C487845:cadrofloxacin; D019392:Cytochrome P-450 CYP2E1
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