Mano Yuji, Usui Takashi, Kamimura Hidetaka
Drug Metabolism Research Laboratories, Astellas Pharma Inc., Itabashi-ku, Tokyo, Japan.
Drug Metab Dispos. 2007 Jul;35(7):1182-7. doi: 10.1124/dmd.107.015347. Epub 2007 Apr 19.
Flurbiprofen is a nonsteroidal anti-inflammatory drug used as a racemic mixture. Although glucuronidation is one of its elimination pathways, the role of UDP-glucuronosyltransferase (UGT) in this process remains to be investigated. Thus, the kinetics of the stereoselective glucuronidation of racemic (R,S)-flurbiprofen by recombinant UGT isozymes and human liver microsomes (HLMs) were investigated, and the major human UGT isozymes involved were identified. UGT1A1, 1A3, 1A9, 2B4, and 2B7 showed glucuronidation activity for both (R)- and (S)-glucuronide, with UGT2B7 possessing the highest activity. UGT2B7 formed the (R)-glucuronide at a rate 2.8-fold higher than that for (S)-glucuronide, whereas the other UGTs had similar formation rates. The glucuronidation of racemic flurbiprofen by HLMs also resulted in the formation of (R)-glucuronide as the dominant form, which occurred to a degree similar to that by recombinant UGT2B7 (2.1 versus 2.8). The formation of (R)-glucuronide correlated significantly with morphine 3-OH glucuronidation (r = 0.96, p < 0.0001), morphine 6-OH glucuronidation (r = 0.91, p < 0.0001), and 3'-azido-3'-deoxythymidine glucuronidation (r = 0.85, p < 0.0001), a reaction catalyzed mainly by UGT2B7, in individual HLMs. In addition, the formation of both glucuronides correlated significantly (r = 0.99, p < 0.0001). Mefenamic acid inhibited the formation of both (R)- and (S)-glucuronide in HLMs with similar IC(50) values (2.0 and 1.7 muM, respectively), which are close to those in recombinant UGT2B7. In conclusion, these findings suggest that the formation of (R)- and (S)-glucuronide from racemic flurbiprofen is catalyzed by the same UGT isozyme, namely UGT2B7.
氟比洛芬是一种用作消旋混合物的非甾体抗炎药。虽然葡萄糖醛酸化是其消除途径之一，但尿苷二磷酸葡萄糖醛酸基转移酶（UGT）在此过程中的作用仍有待研究。因此，研究了重组UGT同工酶和人肝微粒体（HLM）对消旋（R，S）-氟比洛芬进行立体选择性葡萄糖醛酸化的动力学，并确定了主要涉及的人UGT同工酶。UGT1A1、1A3、1A9、2B4和2B7对（R）-和（S）-葡萄糖醛酸酯均表现出葡萄糖醛酸化活性，其中UGT2B7活性最高。UGT2B7形成（R）-葡萄糖醛酸酯的速率比（S）-葡萄糖醛酸酯高2.8倍，而其他UGT的形成速率相似。HLM对消旋氟比洛芬的葡萄糖醛酸化也导致以（R）-葡萄糖醛酸酯作为主要形式形成，其程度与重组UGT2B7相似（分别为2.1和2.8）。在个体HLM中，（R）-葡萄糖醛酸酯的形成与吗啡3-OH葡萄糖醛酸化（r = 0.96，p < 0.0001）、吗啡6-OH葡萄糖醛酸化（r = 0.91，p < 0.0001）和3'-叠氮基-3'-脱氧胸苷葡萄糖醛酸化（r = 0.85，p < 0.0001）显著相关，后一反应主要由UGT2B7催化。此外，两种葡萄糖醛酸酯的形成显著相关（r = 0.99，p < 0.0001）。甲芬那酸抑制HLM中（R）-和（S）-葡萄糖醛酸酯的形成，IC（50）值相似（分别为2.0和1.7μM），这与重组UGT2B7中的值接近。总之，这些发现表明，消旋氟比洛芬形成（R）-和（S）-葡萄糖醛酸酯是由同一UGT同工酶即UGT2B7催化的。
