The inhibitory potencies of non-steroidal antiinflammatory drugs (NSAID) on UDP-glucuronosyltransferase (UGT) 1A1-catalysed estradiol 3beta-glucuronidation (E3G) were investigated in human liver microsomes (HLM). Inhibitory effects of the following seven NSAID were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and niflumic acid. Niflumic acid had the most potent inhibitory effect on E3G with an IC50 value of 22.2 microM in HLM. The IC50 values of diclofenac, diflunisal, indomethacin for E3G were 60.9, 37.8 and 51.5 microM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition. Diclofenac inhibited E3G non-competitively with a Ki value of 112 microM in HLM. The IC50 value of diclofenac for 4-methylumbelliferone glucuronidation in recombinant human UGT1A1 was 57.5 microM, similar to that obtained for E3G using HLM. In conclusion, niflumic acid had the most potent inhibitory effects on UGT1A1-catalysed E3G in HLM among seven NSAID investigated.
2004 John Wiley & Sons, Ltd.