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Research ArticleArticle

Correlation between Bilirubin Glucuronidation and Estradiol-3-Gluronidation in the Presence of Model UDP-Glucuronosyltransferase 1A1 Substrates/Inhibitors

Jin Zhou, Timothy S. Tracy and Rory P. Remmel
Drug Metabolism and Disposition February 2011, 39 (2) 322-329; DOI: https://doi.org/10.1124/dmd.110.035030
Jin Zhou
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Timothy S. Tracy
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Rory P. Remmel
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Abstract

Inhibition of UDP-glucuronosyltransferase (UGT) 1A1-catalyzed bilirubin glucuronidation by drug compounds may potentially be of clinical concern. However, in drug discovery and development settings, bilirubin is less than an ideal in vitro probe for assessing the potential of a chemical entity to inhibit bilirubin glucuronidation. In part, this is due to the propensity of bilirubin to photodegrade and to the instability of its metabolites. To this end, the utility of estradiol-3-glucuronidation as a surrogate in vitro predictor for interactions with bilirubin was evaluated. The glucuronidation kinetics of bilirubin and estradiol were carefully characterized with recombinant UGT1A1 expressed in human embryonic kidney 293 cells. Consistent with previous reports, estradiol-3-glucuronidation displayed sigmoidal kinetics, whereas bilirubin glucuronidation exhibited typical hyperbolic kinetics. The two compounds also mutually inhibited the metabolism of the other. Sixteen UGT1A1 substrates/inhibitors were evaluated as effectors of each reaction. Fourteen compounds inhibited both bilirubin and estradiol glucuronidation. However, two compounds (ethinylestradiol and daidzein) exhibited mixed effects (concentration-dependent activation and inhibition) on estradiol-3-glucuronidation, whereas bilirubin glucuronidation was inhibited by both compounds. In addition, 7-ethyl-10-hydroxycamptothecin, a substrate of UGT1A1 (reported Km = 24 μM) seemed to be a weak inhibitor of bilirubin glucuronidation (IC50 = 356.4 μM) but a partial inhibitor of estradiol-3-glucuronidation. The IC50 values of the inhibitors against estradiol-3-glucuronidation were strongly correlated with IC50 values against bilirubin glucuronidation, resulting in an R2 value of 0.9604 (activator excluded) or 0.8287 (activator included). Thus, estradiol-3-glucuronidation can serve as a good surrogate for predicting inhibition of bilirubin glucuronidation with the caveat that occasionally compounds may demonstrate activation of estradiol-3-glucuronidation.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM063215] (to T.S.T.); and in the form of an investigator-initiated grant from by Bristol-Myers Squibb (to R.P.R.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035030.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    UDPGA
    UDP-glucuronic acid
    SN-38
    7-ethyl-10-hydroxycamptothecin
    OH
    hydroxy
    HPLC
    high-performance liquid chromatography
    HEK
    human embryonic kidney
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry.

  • Received June 28, 2010.
  • Accepted October 25, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (2)
Drug Metabolism and Disposition
Vol. 39, Issue 2
1 Feb 2011
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Research ArticleArticle

Correlation between Bilirubin Glucuronidation and Estradiol-3-Gluronidation in the Presence of Model UDP-Glucuronosyltransferase 1A1 Substrates/Inhibitors

Jin Zhou, Timothy S. Tracy and Rory P. Remmel
Drug Metabolism and Disposition February 1, 2011, 39 (2) 322-329; DOI: https://doi.org/10.1124/dmd.110.035030

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Research ArticleArticle

Correlation between Bilirubin Glucuronidation and Estradiol-3-Gluronidation in the Presence of Model UDP-Glucuronosyltransferase 1A1 Substrates/Inhibitors

Jin Zhou, Timothy S. Tracy and Rory P. Remmel
Drug Metabolism and Disposition February 1, 2011, 39 (2) 322-329; DOI: https://doi.org/10.1124/dmd.110.035030
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