Glucuronidation kinetics of R,S-ketoprofen in adjuvant-induced arthritic rats.
OBJECTIVE
A pharmacokinetic study was carried out in rats to investigate the effect of arthritis on the glucuronidation of the nonsteroidal anti-inflammatory drug ketoprofen.


METHODS
An i.v. bolus dose of R,S-ketoprofen (10 mg/kg) was administered to control (n = 6) and adjuvant-induced arthritic rats (n = 6). All experiments were carried out in bile-exteriorized animals. Concentrations of R- and S-ketoprofen in plasma, bile and urine, and of their glucuronides in bile and urine were determined by HPLC. In a separate series of experiments, the ex vivo plasma protein binding of R- and S-ketoprofen was measured in control and arthritic rats following i.v. administration of R,S-ketoprofen.


RESULTS
As a result of a significant decrease in plasma albumin concentrations in arthritic rats, the unbound fraction of R- and S-ketoprofen was significantly increased (approximately 2-fold) in rats with adjuvant-induced arthritis. Total (i.e., bound plus unbound) plasma clearances of R- and S-ketoprofen were not different in arthritic rats. Unbound plasma clearances of both ketoprofen enantiomers, however, were significantly reduced (by 53% and 61%, respectively). This was due to a significant impairment in the formation of the R- and S-ketoprofen glucuronides. There was no apparent effect of adjuvant-induced arthritis on the chiral inversion of R- to S-ketoprofen.


CONCLUSIONS
Adjuvant-induced arthritis in the rat leads to a significant impairment in the in vivo glucuronidation of R- and S-ketoprofen.
Meunier
C J
CJ
Pharmacokinetics and Drug Metabolism Laboratory, School of Pharmacy, Université Catholique de Louvain, Brussels, Belgium.
Verbeeck
R K
RK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001169:Arthritis, Experimental / Q000378:metabolism*; D001659:Biliary Tract / Q000378:metabolism; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007700:Kinetics; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012709:Serum Albumin; C044223:ketoprofen glucuronide; D007660:Ketoprofen