Purpose. A pharmacokinetic study was carried out in rats to investigate the
effect of arthritis on the glucuronidation of the nonsteroidal antiinflamm
atory drug ketoprofen.
Methods. An iv bolus dose of R,S-ketoprofen (10 mg/kg) was administered to
control (n = 6) and adjuvant-induced arthritic rats (n = 6). All experiment
s were carried out in bile-exteriorized animals. Concentrations of R- and S
-ketoprofen in plasma, bile and urine, and of their glucuronides in bile an
d urine were determined by HPLC. In a separate series of experiments, the e
x vivo plasma protein binding of R- and S-ketoprofen was measured in contro
l and arthritic rats following iv administration of R,S-ketoprofen.
Results. As a result of a significant decrease in plasma albumin concentrat
ions in arthritic rats, the unbound fraction of R- and S-ketoprofen was sig
nificantly increased (approximately a-fold) in rats with adjuvant-induced a
rthritis. Total (i.e., bound plus unbound) plasma clearances of R- and S-ke
toprofen were not different in arthritic rats. Unbound plasma clearances of
both ketoprofen enantiomers, however, were significantly reduced (by 53% a
nd 61%, respectively). This was due to a significant impairment in the form
ation of the R- and S-ketoprofen glucuronides. There was no apparent effect
of adjuvant-induced arthritis on the chiral inversion of R- to S-ketoprofe
n.
Conclusions. Adjuvant-induced arthritis in the rat leads to a significant i
mpairment in the in vivo glucuronidation of R- and S-ketoprofen.