Ogata Kenji, Takamura Norito, Tokunaga Jin, Ikeda Tetsuya, Setoguchi Nao, Tanda Kazuhiro, Yamasaki Tetsuo, Nishio Toyotaka, Kawai Keiichi
Second Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
Division of Neurobiology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Miyazaki, 889-1692, Japan.
Eur J Drug Metab Pharmacokinet. 2016 Apr;41(2):179-86. doi: 10.1007/s13318-014-0248-z. Epub 2014 Dec 24.
Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non-steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration-time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect.
氟比洛芬酯（FPA）是一种注射用产品，是非甾体抗炎药（NSAID）的前体药物。注射后，它迅速水解为活性形式氟比洛芬（FP）。由于频繁注射FPA会导致生理异常，因此需要一种给药策略，以确保单次给药后FP的镇痛效果增强，并减少给药总次数。FP与白蛋白的位点II紧密结合，因此游离（未结合）FP的浓度较低。本研究聚焦于萘丁美酮（一种NSAID前体药物）的活性代谢物6-甲氧基-2-萘乙酸（6-MNA）。我们在大鼠中进行了超滤实验和药代动力学分析，以研究6-MNA对FP与白蛋白结合的抑制作用是否会在体外和体内增加游离FP的浓度。结果表明，6-MNA竞争性抑制FP与白蛋白的结合。当在大鼠中注射6-MNA时，游离FP浓度以及根据游离FP浓度计算的浓度-时间曲线下面积（AUC）显著增加，而总（结合+游离）FP浓度以及根据总FP浓度计算的AUC显著降低。这些发现表明，6-MNA在体内抑制FP的蛋白结合。这表明当与萘丁美酮联合给药时，FPA的注射频率可以降低，因为与药理效应相关的游离FP浓度会增加。
