Meunier C J, Verbeeck R K
Pharmacokinetics and Drug Metabolism Laboratory, School of Pharmacy, Université Catholique de Louvain, Brussels, Belgium.
Pharm Res. 1999 Jul;16(7):1081-6. doi: 10.1023/a:1018996018708.
A pharmacokinetic study was carried out in rats to investigate the effect of arthritis on the glucuronidation of the nonsteroidal anti-inflammatory drug ketoprofen.
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.
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.
Adjuvant-induced arthritis in the rat leads to a significant impairment in the in vivo glucuronidation of R- and S-ketoprofen.
在大鼠中进行一项药代动力学研究，以调查关节炎对非甾体抗炎药酮洛芬葡萄糖醛酸化的影响。
对对照组（n = 6）和佐剂诱导的关节炎大鼠（n = 6）静脉注射大剂量R,S-酮洛芬（10 mg/kg）。所有实验均在胆汁外引流的动物中进行。通过高效液相色谱法测定血浆、胆汁和尿液中R-和S-酮洛芬的浓度，以及胆汁和尿液中它们的葡萄糖醛酸苷的浓度。在另一系列实验中，静脉注射R,S-酮洛芬后，测定对照组和关节炎大鼠体内R-和S-酮洛芬的血浆蛋白结合率。
由于关节炎大鼠血浆白蛋白浓度显著降低，佐剂诱导的关节炎大鼠中R-和S-酮洛芬的游离分数显著增加（约2倍）。关节炎大鼠中R-和S-酮洛芬的总（即结合加游离）血浆清除率无差异。然而，两种酮洛芬对映体的游离血浆清除率均显著降低（分别降低53%和61%）。这是由于R-和S-酮洛芬葡萄糖醛酸苷的形成受到显著损害。佐剂诱导的关节炎对R-酮洛芬向S-酮洛芬的手性转化没有明显影响。
大鼠佐剂诱导的关节炎导致R-和S-酮洛芬体内葡萄糖醛酸化显著受损。
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