Glucuronidation kinetics of R,S-ketoprofen in adjuvant-induced arthritic rats

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.