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

Pharm Res. 1999 Jul;16(7):1081-6. doi: 10.1023/a:1018996018708.

Abstract

Purpose: 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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / blood
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*
  • Anti-Inflammatory Agents, Non-Steroidal / urine
  • Arthritis, Experimental / metabolism*
  • Biliary Tract / metabolism
  • Ketoprofen / analogs & derivatives*
  • Ketoprofen / blood
  • Ketoprofen / pharmacokinetics*
  • Ketoprofen / urine
  • Kinetics
  • Male
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Serum Albumin / metabolism
  • Stereoisomerism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Serum Albumin
  • ketoprofen glucuronide
  • Ketoprofen