title: Studies on the reactivity of acyl glucuronides--I. Phenolic glucuronidation of isomers of diflunisal acyl glucuronide in the rat.
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--less than 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.
authors.affiliation: Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
authors.forename: A R
authors.initials: AR
authors.lastname: King
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004061:Diflunisal / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D005965:Glucuronates / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D005965:Glucuronates; C041945:diflunisal glucuronide ether; C041944:diflunisal glucuronide ester; D004061:Diflunisal; D005966:Glucuronidase