Inhibition of the rat hepatic microsomal flurbiprofen acyl glucuronidation by bile acids

Nariyasu Mano, Takaaki Goto, Ayako Nikaido, Takashi Narui, Junichi Goto

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Glucuronidation of carboxylic acids, primarily catalyzed by hepatic UDP-glucuronosyltransferases, is an important phase II metabolic pathway functioning in detoxification. Acyl glucuronides of 2-aryl propionates, however, can form covalently bound protein adducts, which may generate hypersensitive reactions. We previously identified and quantified R- and S-flurbiprofen acyl glucuronides in human urine following the oral administration of flurbiprofen by liquid chromatography/electrospray ionization mass spectrometry. Recent studies also demonstrated the inhibitory effect of bile acids and their metabolites toward rat hepatic bile acid acyl glucuronidation, which may also be the target of the flurbiprofen isoenzyme. We therefore performed a kinetic analysis of rat hepatic flurbiprofen UDP-glucuronosyltransferase using bisubstrate kinetic analysis and inhibition studies. The results indicated that both bile acid and its metabolites clearly inhibited flurbiprofen acyl glucuronidation. The inhibitory effect on flurbiprofen was more efficient than the effect seen on bile acid acyl glucuronidation. Unconjugated, glycine- and taurine-conjugated chenodeoxycholic acids inhibited glucuronidation using a noncompetitive mechanism, whereas the inhibition by chenodeoxycholic acid 24-acyl glucuronide occurred according to a mixed type mechanism. The inhibition by bile acids and their metabolites may be responsible for the suppression of the toxicity of carboxy-linked glucuronides.

Original languageEnglish
Pages (from-to)2098-2108
Number of pages11
JournalJournal of Pharmaceutical Sciences
Issue number10
Publication statusPublished - 2003 Oct 1


  • Acyl glucuronide
  • Bile acid
  • Detoxification mechanism
  • Flurbiprofen
  • Inhibition

ASJC Scopus subject areas

  • Pharmaceutical Science


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