title: Inhibitory effect of ciprofloxacin on β-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide.
abstract: The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β-glucuronidase-mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 µm. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase.
authors.affiliation: Department of Pharmacy, Fukui University Hospital, Faculty of Medical Sciences Fukui University, Yoshida-gun, Fukui, 910-1193, Japan; Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kodawara
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yano
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Mikio
authors.initials: M
authors.lastname: Masada
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015365:Enoxacin / Q000494:pharmacology; D004764:Enterohepatic Circulation / Q000187:drug effects; D005966:Glucuronidase / Q000378:metabolism*; D020719:Glucuronides / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D064704:Levofloxacin / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D015242:Ofloxacin / Q000494:pharmacology; D010635:Phenolphthaleins / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D020719:Glucuronides; D007166:Immunosuppressive Agents; D010635:Phenolphthaleins; C016651:phenolphthalein glucuronide; D015365:Enoxacin; C113145:mycophenolic acid glucuronide; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D005966:Glucuronidase; D009173:Mycophenolic Acid
keywords: MPAG; ciprofloxacin; drug interaction; β-glucuronidase