Absence of phenolic glucuronidation and enhanced hydroxylation of diflunisal in the homozygous Gunn rat

Abstract

1. 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.