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Glucuronidation Kinetics of R,S-Ketoprofen in Adjuvant-Induced Arthritic Rats

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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 iv 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 iv 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.

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  1. Pharmacokinetics and Drug Metabolism Laboratory, School of Pharmacy, Université Catholique de Louvain, (UCL), Brussels, Belgium

    Christine J. Meunier & Roger K. Verbeeck

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  1. Christine J. Meunier
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  2. Roger K. Verbeeck
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Correspondence to Roger K. Verbeeck.

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Meunier, C.J., Verbeeck, R.K. Glucuronidation Kinetics of R,S-Ketoprofen in Adjuvant-Induced Arthritic Rats. Pharm Res 16, 1081–1086 (1999). https://doi.org/10.1023/A:1018996018708

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