Angus R King

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A major metabolite of diflunisal (DF) is its reactive acyl glucuronide conjugate (DAG) which can undergo hydrolysis (regeneration of DF), intramolecular rearrangement (isomerization via acyl migration) and intermolecular reactions with nucleophiles. We have compared the fate of DAG and its individual 2-, 3- and 4-O-acyl positional isomers (at ca. 55(More)
The incubation of 1-O-clofibryl glucuronide (1-O-CAG), a metabolite of clofibrate, with glutathione (GSH) resulted in the appearance of a new peak when analyzed by HPLC. The use of HPLC coupled to electrospray-MS permitted the identification of the peak as S-(p-chlorophenoxy-2-methylpropanoyl)glutathione (CA-SG), formed by nucleophilic displacement of the(More)
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(More)
Many non-steroidal anti-inflammatory drugs (NSAIDs) which form acyl glucuronide conjugates as major metabolites have shown an antiproliferative effect on colorectal tumors. This study assesses the extent to which rearrangement of an acyl glucuronide metabolite of a model NSAID into beta-glucuronidase-resistant isomers facilitates its passage through the(More)
Several nations have adopted hardness-modified copper (Cu) guidelines for protecting freshwater biota. However, there is a lack of good quality data and mechanistic understanding on the effects of true water hardness (calcium (Ca) and magnesium (Mg)) on the bioavailability and toxicity of Cu to freshwater biota, particularly macrophytes. This study(More)
Reactivity of glucuronide and sulfate conjugates was taken into account in development of a simple isocratic HPLC method for direct assay of diflunisal (DF) and its acyl glucuronide (DAG), phenolic glucuronide (DPG), and sulfate (DS) conjugates. Whereas DPG was stable over the pH range 0-9, DAG was highly labile at neutral to slightly alkaline pH,(More)
1. A new metabolite of diflunisal, a hydroxy derivative, has been identified in rat and human urine following administration of diflunisal. 2. This hydroxy metabolite of diflunisal is excreted in urine of both species as a polar conjugate, most likely a sulphate. 3. Attempts to isolate the polar conjugate in pure form were unsuccessful due to its rapid(More)
1. In five healthy male volunteers given multiple doses of diflunisal (DF), renal clearances (CLR) of the acyl glucuronide (DAG), phenolic glucuronide (DPG) and sulphate (DS) conjugates were about 42, 25 and 13 ml min-1, respectively. 2. These relatively low CLR values are probably due largely to the very high plasma protein binding of the conjugates, found(More)
During a carbamazepine (CBZ) relative bioavailability study involving tablets and a syrup preparation, salivary drug concentrations appeared disproportionately high relative to simultaneous plasma drug concentrations in the first 2-3 h after oral drug intake. This raised the suspicion of contamination of saliva by retention of drug in the mouth. In a(More)
Acyl glucuronides have been shown to be reactive electrophilic metabolites capable of undergoing hydrolysis, rearrangement (isomerization via acyl migration) and covalent binding reactions to plasma protein. The present study was undertaken to explore the occurrence and extent of in vivo formation of covalent adducts of diflunisal (DF), a salicylate(More)