Glucuronidation of diflunisal in liver and kidney microsomes of rat
and man.
Brunelle FM, Verbeeck RK
Pharmacokinetics Laboratory, Catholic University of Louvain, Brussels,
Belgium.
1. The glucuronidation of diflunisal to its phenolic (DPG) and acyl
glucuronide (DAG) was measured in vitro using microsomes prepared from
rat (n = 4) and human (n = 6) liver and kidney tissue. UGT activities towards
bilirubin, 4-nitrophenol and (-)-morphine were also determined. 2. beta-Glucuronidase
activity towards phenolphthalein glucuronide was much lower in microsomes
prepared from human liver (45.2 +/- 3.1 Fishman Units/mg protein), human
kidney (22.0 +/- 3.3 FU/mg), and rat kidney (25.1 +/- 2.5 FU/mg) as compared
with rat liver (118.7 +/- 8.8 FU/mg). 3. The formation rate of DAG significantly
increased when saccharo-1,4-lactone, a beta-glucuronidase inhibitor, was
added to the rat liver microsomal incubation medium. beta-Glucuronidase
inhibition, however, had little effect on the formation rate of DAG in
human liver microsomes, and no effect in rat and human kidney microsomes.
The formation of DPG was not affected by the microsomal beta-glucuronidase
activity. 4. Unlike rat kidney microsomes, which only formed DAG, human
kidney microsomes formed both diflunisal glucuronides. Formation of both
diflunisal glucuronides in human kidney microsomes (Vmax = 0.97 +/- 0.21
and 0.27 +/- 0.07 nmol/min/mg for formation of DAG and DPG respectively)
represented 60-70% of the activity found in liver microsomes (Vmax = 1.58
+/- 0.32 and 0.40 +/- 0.08 nmol/min/mg for formation of DAG and DPG respectively).
5. These results demonstrate that the in vitro glucuronidation rate of
diflunisal may be affected by the microsomal beta-glucuronidase activity
particularly when using rat liver microsomes. Our results also demonstrate
that the human kidney has an important UGT-activity towards diflunisal.
PMID: 8867997, UI: 97021637