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Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Objective

We characterized the kinetics of indomethacin glucuronidation by recombinant UDP-glucuronosyltransferase (UGT) isozymes and human liver microsomes (HLM) and identified the human UGT isozymes involved.

Methods

Indomethacin glucuronidation was investigated using HLM and recombinant human UGT isozymes. Human UGTs involved in indomethacin glucuronidation were assessed in kinetic studies, chemical inhibition studies, and correlation studies.

Results

Among the UGT isozymes investigated, UGT1A1, 1A3, 1A9, and 2B7 showed glucuronidation activity for indomethacin, with UGT1A9 possessing the highest activity, followed by UGT2B7. Glucuronidation of indomethacin by recombinant UGT1A9 and 2B7 showed substrate inhibition kinetics with K m values of 35 and 32 μM, respectively. The glucuronidation of indomethacin was significantly correlated with morphine 3OH-glucuronidation (r = 0.69, p < 0.05) and 3′-azido-3′-deoxythymidine glucuronidation (r = 0.82, p < 0.05), a reaction mainly catalyzed by UGT2B7. Propofol inhibited indomethacin glucuronidation in HLM with an IC50 value of 248 μM, which is between the IC50 value in recombinant UGT1A9 (106 μM) and UGT2B7 (> 400 μM).

Conclusions

These findings suggest that UGT2B7 plays a predominant role in indomethacin glucuronidation in the human liver and that UGT1A9 is partially involved.

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Authors and Affiliations

  1. Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8, Azusawa 1-chome, Itabashi-ku, Tokyo, 174-8511, Japan

    Yuji Mano, Takashi Usui & Hidetaka Kamimura

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  1. Yuji Mano
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  2. Takashi Usui
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  3. Hidetaka Kamimura
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Correspondence to Yuji Mano.

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Mano, Y., Usui, T. & Kamimura, H. Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol 63, 289–296 (2007). https://doi.org/10.1007/s00228-007-0261-0

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  • DOI: https://doi.org/10.1007/s00228-007-0261-0

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