Brunelle FM, Verbeeck RK
Laboratory of Pharmacokinetics, School of Pharmacy, Catholic University
of Louvain, Brussels, Belgium.
The role of beta-glucuronidase catalyzed hydrolysis of glucuronides
on the in vivo disposition kinetics of xenobiotics was studied in the rat.
The metabolic disposition kinetics of diflunisal, a compound undergoing
transformation to an acyl and phenyl glucuronide, were studied in rats
under control conditions and following administration of D-glucaro-1,4-lactone,
a potent and specific beta-glucuronidase inhibitor. D-glucaro-1,4-lactone
treatment resulted in a significant decrease in beta-glucuronidase activity
in plasma, urine, and hepatic microsomes. Total (i.e. urinary and biliary)
recovery of the acyl glucuronide following i.v. injection of diflunisal
(10 mg/kg) was significantly higher in D-glucaro-1,4-lactone treated rats
(41 +/- 3%, n=6) compared to control rats (29 +/- 2%, n=6) whereas for
diflunisal phenyl glucuronide this total recovery was very similar in both
groups of rats (16.0 +/- 1.0% vs. 18.0 +/- 0.2%, n=6, respectively). The
partial clearance of diflunisal associated with the formation of the acyl
glucuronide was significantly higher in D-glucaro-1,4-lactone treated rats
(0.413 +/- 0.024 ml/min/kg) compared to control animals (0.269 +/- 0.042
ml/min/kg). The partial clearance related to the formation of the phenyl
glucuronide, on the contrary, was not significantly affected by D-glucaro-1,4-lactone
treatment. These results shows that the in vivo glucuronidation of diflunisal
to the acyl glucuronide, unlike diflunisal glucuronidation to the phenyl
glucuronide, is subject to a futile conjugation-deconjugation cycle. Such
futile cycling may have significant therapeutic and toxic implications.
PMID: 9180355, UI: 97324186