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 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.
Mano
Yuji
Y
Drug Metabolism Research Laboratories, Astellas Pharma Inc., Itabashi-ku, Tokyo, Japan. yuuji.mano@jp.astellas.com
Usui
Takashi
T
Kamimura
Hidetaka
H
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000737:chemistry / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008528:Mefenamic Acid / Q000494:pharmacology; D050217:Metabolic Detoxication, Phase II; D008862:Microsomes, Liver / Q000201:enzymology; D009020:Morphine / Q000378:metabolism; D009022:Morphine Derivatives / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D000090264:UDP-Glucuronosyltransferase 1A9; D015215:Zidovudine / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D005480:Flurbiprofen; D020719:Glucuronides; D014453:Glucuronosyltransferase; D008528:Mefenamic Acid; D009020:Morphine; D009022:Morphine Derivatives; D011994:Recombinant Proteins; D000090264:UDP-Glucuronosyltransferase 1A9; D015215:Zidovudine; D000099148:UGT1A1 Enzyme; C067409:3'amino-3'-deoxy-5'-glucopyranuronosylthymidine; C035349:morphine-6-glucuronide; C122075:UDP-glucuronosyltransferase, UGT1A3; C491474:UGT2B7 protein, human; C486404:UGT2B4 protein, human; C018108:morphine-3-glucuronide