Nagao Tomoaki, Tanino Tadatoshi, Iwaki Masahiro
Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Osaka, Japan.
Chirality. 2003 May 15;15(5):423-8. doi: 10.1002/chir.10227.
To determine the effect of arthritis on the disposition of flurbiprofen (FP) and its acyl glucuronide (FPG) as well as formation of covalent adducts with plasma protein, a pharmacokinetic study was carried out in adjuvant-induced arthritic (AA) rats. In control animals the pharmacokinetics of FP were stereoselective following intravenous bolus injection of rac-FP: (-)-(R)-FP showed higher plasma clearance (CL(tot)) and shorter mean residence time (MRT) compared to (+)-(S)-FP. The CL(tot) and clearance for the glucuronide formation (CL(glu)) of both enantiomers in AA rats were extremely increased compared to those in control rats. Increased total clearance in AA rats was due, at least in part, to a remarkable increase in the plasma unbound fraction of FP, consistent with a decrease in the plasma albumin level. The yield of covalent binding of FP to plasma protein in AA rats was less than that in controls, being consistent with the decrease in the plasma acyl glucuronide level.
为了确定关节炎对氟比洛芬（FP）及其酰基葡萄糖醛酸苷（FPG）的处置以及与血浆蛋白形成共价加合物的影响，在佐剂诱导的关节炎（AA）大鼠中进行了一项药代动力学研究。在对照动物中，静脉推注消旋氟比洛芬后，氟比洛芬的药代动力学具有立体选择性：与（+）-（S）-氟比洛芬相比，（-）-（R）-氟比洛芬表现出更高的血浆清除率（CL（tot））和更短的平均驻留时间（MRT）。与对照大鼠相比，AA大鼠中两种对映体的葡萄糖醛酸苷形成清除率（CL（glu））和CL（tot）均显著增加。AA大鼠总清除率的增加至少部分归因于氟比洛芬血浆未结合分数的显著增加，这与血浆白蛋白水平的降低一致。AA大鼠中氟比洛芬与血浆蛋白共价结合的产率低于对照组，这与血浆酰基葡萄糖醛酸苷水平的降低一致。
