Studies on the reactivity of acyl glucuronides-I. Phenolic glucuronidation of isomers of diflunisal acyl glucuronide in the rat

King A.R. and Dickinson R.G. (1991) Studies on the reactivity of acyl glucuronides-I. Phenolic glucuronidation of isomers of diflunisal acyl glucuronide in the rat. Biochemical Pharmacology, 42 12: 2289-2299. doi:10.1016/0006-2952(91)90232-T


Author King A.R.
Dickinson R.G.
Title Studies on the reactivity of acyl glucuronides-I. Phenolic glucuronidation of isomers of diflunisal acyl glucuronide in the rat
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
Publication date 1991-11-27
Sub-type Article (original research)
DOI 10.1016/0006-2952(91)90232-T
Volume 42
Issue 12
Start page 2289
End page 2299
Total pages 11
Subject 3004 Pharmacology
Abstract Diflunisal (DF) is metabolized primarily to its acyl glucuronide (DAG), phenolic glucuronide (DPG) and sulphate (DS) conjugates. Whereas DPG and DS are stable at physiological pH, DAG is unstable, undergoing hydrolysis (regeneration of DF) and rearrangement (intramolecular acyl migration to the 2-, 3- and 4-O-acyl-positional isomers). We have compared the in vivo disposition of DAG with that of an equimolar mixture of its three isomers after i.v. administration at 10 mg DF equivalents/kg to conscious, bile-exteriorized rats. After dosing with DAG, excretion in urine and bile (46% as DAG), hydrolysis (as assessed by recovery of 9% DPG and 8% DS resulting from reconjugation of liberated DF) and rearrangement (17% recovery as isomers of DAG) were important pathways. Highly polar metabolites excreted almost exclusively in bile and accounting for 13% of the dose were identified as an approximate 4:1 mixture of the 2- and 3-O-isomers of DAG which had been glucuronidated at the phenolic function of the salicylate ring i.e. "diglucuronides" of DF. Evidence for trace quantities only of the phenolic glucuronides of the 4-O-isomer of DAG, and of DAG itself, was found. After dosing rats with an equimolar mixture of the isomers, 52% was recovered (as the isomers) in urine and bile in 6 hr. Hydrolysis was less important - <3% (total) of the dose was recovered as DPG and DS. The phenolic glucuronides of the 2- and 3-O-isomers (ratio ca. 3:7) accounted for 37%. Evidence for appreciable formation of the phenolic glucuronide of the 4-O-isomer was not found. In one rat dosed with DPG, there was no evidence for further glucuronidation of the salicylate ring at its carboxy function. The data suggest that the 2- and 3-O-isomers of DAG, but not the 4-O-isomer, DAG itself or DPG, are good substrates for further glucuronidation.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import
 
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