Contrasting systemic stabilities of the acyl and phenolic glucuronides of diflunisal in the rat

Abstract

1. Diflunisal (DF) is metabolized in humans and rats primarily to its acyl glucuronide, phenolic glucuronide and sulphate conjugates.

2. After i.v. administration of DF acyl glucuronide to pentobarbitone-anaesthetized rats, DF and its phenolic glucuronide and sulphate conjugates appeared rapidly in plasma, indicating ready systemic hydrolysis of the acyl glucuronide and subsequent biotransformation of liberated DF.

3. Approximately 72% of the acyl glucuronide dose was recovered in bile and urine over 6 h: 52% as acyl glucuronide, 6% as phenolic glucuronide, 5% as sulphate, and 8% as isomers of the acyl glucuronide arising from intramolecular acyl migration.

4. Blockage of excretion routes by ligation of the ureters, bile duct, and both ureters and bile duct, decreased plasma clearance of the acyl glucuronide from 7.8 ml/min per kg to 6.0, 3.2 and 2.2 ml/min per kg respectively, and increased the apparent terminal plasma half-life of DF from 2.1 h to 2.6, 3.4 and 6.3 h, respectively.

5. By contrast, DF phenolic glucuronide was quite stable after i.v. administration at the same dose.

6. This study shows that systemic cycling between DF and its acyl glucuronide exists in the rat in vivo, with portions of each cycle of unstable acyl glucuronide through DF yielding stable phenolic glucuronide and (presumptively stable) sulphate conjugate.