Predominant contribution of UDP-glucuronosyltransferase 2B7 in the glucuronidation of racemic flurbiprofen in the human liver

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 IC50 values ( 2.0 and 1.7 mu M, 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.