Absence of phenolic glucuronidation and enhanced hydroxylation of diflunisal in the homozygous Gunn rat
1991; Taylor & Francis; Volume: 21; Issue: 11 Linguagem: Inglês
10.3109/00498259109044403
ISSN1366-5928
AutoresR. G. Dickinson, Roger K. Verbeeck, Andrew King,
Tópico(s)Inflammatory mediators and NSAID effects
Resumo1. The disposition of diflunisal (DF) was investigated in bile-exteriorized and intact homozygous Gunn rats given 10 and 50 mg/kg doses i.v. and in Wistar rats given 10mg/kg doses i.v.2. In Gunn rats, DF sulphate, DF acyl glucuronide, and a hitherto unidentified metabolite of DF, a conjugate of 3-hydroxy-DF, were identified as the major metabolites, accounting for ∼ 37%, 16% and 11% respectively of 10mg/kg doses and 35%, 24% and 15% respectively of 50 mg/kg doses in bile-exteriorized animals. There was no evidence for formation of DF phenolic glucuronide.3. Total plasma clearance of DF and formation clearances of DF to DF sulphate and 3-hydroxy-DF were little affected by increase of dose from 10 to 50mg DF/kg, whereas formation clearance of DF to DF acyl glucuronide was increased, but not significantly.4. In Gunn rats with undisturbed bile flow into the gut, recoveries of DF sulphate and total 3-hydroxy-DF in urine increased to ∼48% and 25% dose respectively at the expense of DF acyl glucuronide through enterohepatic recirculation.5. In bile-exteriorized Wistar rats, DF phenolic glucuronide, DF acyl glucuronide, DF sulphate and 3-hydroxy-DF accounted for 16%, 27%, 14% and 2%, respectively, of 10mg/kg doses. In intact Wistar rats, urinary recoveries of the metabolites were 15%, 13%, 23% and 5%, respectively.6. Thus in comparison to Wistar rats, phenolic glucuronidation of DF was absent or negligible in homozygous Gunn rats, acyl glucuronidation was significantly decreased, sulphation was unchanged, and the 3-hydroxylation of DF was significantly enhanced.
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