Premium
Inhibitory effect of ciprofloxacin on β‐glucuronidase‐mediated deconjugation of mycophenolic acid glucuronide
Author(s) -
Kodawara Takaaki,
Masuda Satohiro,
Yano Yoshitaka,
Matsubara Kazuo,
Nakamura Toshiaki,
Masada Mikio
Publication year - 2014
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1894
Subject(s) - chemistry , ciprofloxacin , glucuronidase , glucuronide , norfloxacin , pharmacology , ofloxacin , pharmacokinetics , quinolone , enterohepatic circulation , antibiotics , biochemistry , enzyme , metabolism , biology
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 (IC 50 ) value of 30.4 µ m . 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. Copyright © 2014 John Wiley & Sons, Ltd.