Conjugation of desmethylnaproxen in the rat - A novel acyl glucuronide-sulfate diconjugate as a major biliary metabolite

Jaggi, R., Addison, R. S., King, A. R., Suthers, B. D. and Dickinson, R. G. (2002) Conjugation of desmethylnaproxen in the rat - A novel acyl glucuronide-sulfate diconjugate as a major biliary metabolite. Drug Metabolism and Disposition, 30 2: 161-166. doi:10.1124/dmd.30.2.161


Author Jaggi, R.
Addison, R. S.
King, A. R.
Suthers, B. D.
Dickinson, R. G.
Title Conjugation of desmethylnaproxen in the rat - A novel acyl glucuronide-sulfate diconjugate as a major biliary metabolite
Journal name Drug Metabolism and Disposition   Check publisher's open access policy
ISSN 0090-9556
1521-009X
Publication date 2002-02-01
Sub-type Article (original research)
DOI 10.1124/dmd.30.2.161
Volume 30
Issue 2
Start page 161
End page 166
Total pages 6
Editor J. R. Halpert
Place of publication Bethesda, U.S.A.
Publisher American Society of Pharmacology Experimental Therapeutics
Collection year 2002
Language eng
Subject C1
320307 Medical Biochemistry - Other
730113 Digestive system and disorders
1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract
The nonsteroidal anti-inflammatory drug naproxen is primarily metabolized in humans by acyl glucuronidation to form naproxen acyl glucuronide and by O-dealkylation to form 6-O-desmethylnaproxen (DMN). DMN contains both carboxy and phenolic groups and has been shown to form acyl glucuronide and sulfate conjugates. This project aimed to investigate whether DMN formed a phenolic glucuronide and diglucuronide(s) (with both the carboxy and phenolic groups glucuronidated). Male Sprague-Dawley rats (300-350 g) with exteriorized bile flow were dosed i.v. with DMN at 50 mg/kg. Four major DMN-related peaks were detected in bile by high-performance liquid chromatography (HPLC) analysis at 225 nm, including the known acyl glucuronide and sulfate conjugates. Selective hydrolyses using acidic and alkaline conditions and digestion with beta-glucuronidase allowed tentative identification of the two unknown peaks as the phenolic glucuronide of DMN and a novel acyl glucuronide-sulfate diconjugate of DMN (i.e., formed by sulfonation of the phenolic group and glucuronidation of the carboxy group). The identities were confirmed by liquid chromatography-tandem mass spectrometry analysis of individual HPLC fractions. Total recovery of the DMN dose was approximately 80%, with the sulfate conjugate (50%) and unchanged DMN (10%) being excreted predominantly in urine and the acyl glucuronide (10%), phenolic glucuronide (6%), and acyl glucuronide-sulfate diconjugate (4%) being excreted predominantly or exclusively in bile. No evidence for a diglucuronide metabolite of DMN was found in either bile or urine of the DMN-dosed rats.
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics
Keyword Naproxen
Desmethylnaproxen (DMN)
Pharmacokinetics
Spectrometry
Biliary metabolite
Glucuronide-sulfate diconjugate
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 19 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 14 Aug 2007, 17:32:46 EST