Received for publication February 23, 2007.
Revised April 4, 2007.
Accepted for publication April 16, 2007.

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

Abstract

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) involved in this process remains to be investigated. Thus, the kinetics of the stereoselective glucuronidation of racemic (R,S)-flurbiprofen by recombinant UDP-glucuronosyltransferase (UGT) isozymes and human liver microsomes (HLM) 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, while the other UGTs had similar formation rates. The glucuronidation of racemic flurbiprofen by HLM 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 vs. 2.8). The formation of (R)-glucuronide correlated significantly with morphine 3OH-glucuronidation (r = 0.96, p < 0.0001), morphine 6OH-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 HLM. 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 HLM with similar IC₅₀ values (2.0 and 1.7 µM, 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.

Key words: glucuronidation, UDP glucuronyltransferases

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