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

• Published in: Drug metabolism and disposition Vol. 30; no. 2; pp. 161 - 166
• Main Authors: JAGGI, R, ADDISON, R. S, KING, A. R, SUTHERS, B. D, DICKINSON, R. G
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.2002
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Bile - metabolism; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Glucuronides - metabolism; Male; Medical sciences; Naproxen - analogs & derivatives; Naproxen - chemistry; Naproxen - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sulfates - metabolism; Urine; Intravenous administration; Rat; Digestive system; Metabolite; Dealkylation; Liver; Rodentia; Glucuronic acid conjugation; Metabolism; Glucuroconjugate; Blood plasma; Non steroidal antiinflammatory agent; Vertebrata; Mammalia; Animal; Naproxen; Arylpropionic acid derivatives; Conjugated compound; Pharmacokinetics; Bile
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.30.2.161

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.