1: Eur J Clin Pharmacol 1995;47(6):519-23
Effect of probenecid on the formation and elimination kinetics of the sulphate
and glucuronide conjugates of diflunisal.
Macdonald JI, Wallace SM, Herman RJ, Verbeeck RK
Catholic University of Louvain, School of Pharmacy, Brussels, Belgium.
The effect of probenecid on the pharmacokinetics of diflunisal and its
glucuronide and sulphate conjugates was studied in 8 healthy volunteers.
Diflunisal 250 mg b.d. was administered p.o. for 15 days and its steady
state pharmacokinetics was evaluated on Day 16 after the last dose (control
phase). Probenecid 500 mg b.d. was co-administered throughout the entire
study period in the treatment phase of the study. The steady state plasma
concentration of diflunisal was significantly higher during the probenecid
treatment phase as compared to the control phase (104.0 vs. 63.1 micrograms.ml-1).
This was the result of a significant decrease in the plasma clearance of
diflunisal from 5.8 (control) to 3.4 ml.min-1 (probenecid co-administration).
The metabolite formation clearances of both glucuronides were significantly
decreased by probenecid, -45% and -54% for the phenolic and acyl glucuronide,
respectively. The metabolite formation clearance of the sulphate conjugate
was not affected by probenecid coadministration. Steady state plasma concentrations
of the sulphate and glucuronide conjugates of diflunisal were 2.5- to 3.1-fold
higher during probenecid co-administration, due to a significant reduction
in the renal clearance of the three diflunisal conjugates. Probenecid also
reduced the plasma protein binding of diflunisal, but only to a minor extent;
the unbound plasma fraction of diflunisal at steady state averaged between
5 and 30% higher during probenecid co-administration.
PMID: 7768255, UI: 95285854